This document summarizes porphyrin and heme biosynthesis and catabolism. It describes how porphyrins readily bind metal ions like iron to form heme. Heme is the prosthetic group in hemoglobin and other hemeproteins. The liver and bone marrow are the main sites of heme synthesis. Heme is synthesized through a series of reactions starting from glycine and succinyl-CoA, and ending with the insertion of iron into protoporphyrin IX. After 120 days, old red blood cells are broken down by the liver and spleen, releasing heme which is degraded into biliverdin and then bilirubin. Bilirubin is transported to the liver and conjugated for excretion
This document outlines the steps in the synthesis of heme from succinyl CoA and glycine. Heme synthesis involves 10 enzymatic steps that convert succinyl CoA and glycine into protoporphyrin IX, which is then combined with iron by ferrochelatase to produce heme. Key intermediates include δ-aminolevulinate, porphobilinogen, uroporphyrinogen III, coproporphyrinogen III, and protoporphyrinogen III.
Porphyrins are cyclic organic compounds that are precursors to important enzymes and pigments like heme, chlorophyll, and cytochromes. Heme synthesis involves multiple steps starting with the condensation of glycine and succinyl-CoA to form delta-aminolevulinic acid, followed by further reactions to form porphobilinogen, uroporphyrinogen III, protoporphyrin IX, and finally heme upon chelation with iron. Porphyrin metabolism is related to chromoproteins like hemoglobin, methemoglobin, sulfhemoglobin, carboxyhemoglobin, metalbumin, and myoglobin which contain heme and transport or store oxygen in vertebrates and some
This document provides information on heme synthesis and disorders of heme synthesis (porphyrias). It describes the 7 step process of heme biosynthesis, which takes place partly in the cytoplasm and mitochondria. The key steps involve the formation of porphobilinogen (PBG), uroporphyrinogen, coproporphyrinogen, protoporphyrinogen, and finally heme through the insertion of iron. Regulation and some specific porphyrias are also outlined, including acute intermittent porphyria, congenital erythropoietic porphyria, porphyria cutanea tarda, hereditary coproporphyria, and variegate porphyria.
Heme Biosynthesis and Its disorders (Porphyria)Ashok Katta
Hemoglobin is a protein in red blood cells that transports oxygen and carbon dioxide throughout the body. It is made up of four subunits, each containing a heme group with iron at its center. Heme biosynthesis is a multi-step pathway that takes place in the mitochondria and cytoplasm, starting from succinyl-CoA and glycine and resulting in protoporphyrin with iron inserted at the final step to form heme. Regulation of heme biosynthesis occurs through feedback inhibition of the rate-limiting enzyme ALA synthase by heme levels. Deficiencies in the heme biosynthesis pathway can cause various types of porphyrias, a group of rare genetic disorders characterized by neurological and skin abnormalities.
Biosynthesis and degradation of porphyrin and hemesountharya Sen s
This document summarizes the biosynthesis and degradation of porphyrin and heme. It discusses how glycine and succinyl CoA are condensed to form δ-aminolevulinate, the starting material for porphyrin synthesis. Four molecules of porphobilinogen then condense to form the porphyrin ring. A series of reactions incorporates iron to form heme. Heme is degraded through heme oxygenase to form biliverdin and bilirubin, which is transported to the liver bound to albumin.
Content :-
What is porphyrin?
Biosynthesis of porphyrin (heme)
Site
Reactions
Regulation
Degradation of heme
Site
Reactions
Reference
What is Porphyrin?
Porphyrins are cyclic compound formed by the linkage of four pyrrole rings through methyne(=HC-)bridges.
Structure of hemoglobin & chlorophyll
Examples of some important humanand animal hemoproteins.
Biosynthesis of heme
Site of biosynthesis:-
-Liver (hepatocyte) & Bone Marrow
( erythryoid producing cells )
2) ALA dehydratase :-
The substrates are two molecules of ALA.
The product is porphobilinogen, the first pyrrole.
ALA dehydratase is a -SH containing enzyme.
It is very susceptible to inhibition by lead.
3) Uroporphyrinogen I synthase and uroporphyrinogen IIIcosynthase
Production of uroporphyrinogen III requires two enzymes.The substrates are four molecules of porphobilinogen.
4) Uroporphyrinogen decarboxylase:-
Decarboxylates the acetic acid groups, converting them to methyl groups.
5) Coproporphyrinogen III oxidase:-
Catalyzes the conversion of two propionic acid groups to vinyl groups
6) Protoporphyrinogen IX oxidase:-
Protoporphyrinogen IX oxidase converts the methylene bridges between the pyrrole rings to methenyl bridges.
7) Ferrochelatase:-
Ferrochelatase adds Fe++ to protoporphyrin IX, forming heme.
• The enzyme requires Fe++, ascorbic acid and cysteine (reducing agents).
• Ferrochelatase is inhibited by lead.
Regulation of heme synthesis
Feedback regulation:- heme is a feedback inhibitor of ALA synthase. ALA synthase occurs in both hepatic (ALAS 1) and erythroid (ALAS 2) forms.
Effects of drugs and steroids:- Certain drugs and steroids can increase heme synthesis via increased production of the ratelimiting enzyme, ALA synthase
Substrate availability:- Fe++ must be available for ferrochelatase.
Degradation of heme
Site of Degradation :-
- cells of the reticulo endothelial system in spleen, liver and bone marrow
Heme Degradation
Most of the heme which is degraded comes from hemoglobin in red blood cells, which have a life span of about 120 days.
There is thus a turnover of about 6 g/day of hemoglobin.
Normally , senescent red blood cells and heme from other sources are engulfed by cells of the reticuloendothelial system.
The globin is recycled or converted into amino acids, which in turn are recycled or catabolized as required.
Heme is oxidized.
Microsomal heme oxygenase system
Transport of bilirubin in Plasma
Bilirubin on release from macrophages circulates as unconjugated bilirubin in plasma tightly bound to albumin.
HARPER’S ILLUSTRATED BIOCHEMISTRY (28TH EDITION) by robert murray,david A.bender,peter j kennekky,victor w rodwell,p.antony weil.(page No-271)
Biochemistry Lippincott’s Illustrated Reviews by Richard Harvey& Denise Ferrier
This document outlines the steps in the synthesis of heme from succinyl CoA and glycine. Heme synthesis involves 10 enzymatic steps that convert succinyl CoA and glycine into protoporphyrin IX, which is then combined with iron by ferrochelatase to produce heme. Key intermediates include δ-aminolevulinate, porphobilinogen, uroporphyrinogen III, coproporphyrinogen III, and protoporphyrinogen III.
Porphyrins are cyclic organic compounds that are precursors to important enzymes and pigments like heme, chlorophyll, and cytochromes. Heme synthesis involves multiple steps starting with the condensation of glycine and succinyl-CoA to form delta-aminolevulinic acid, followed by further reactions to form porphobilinogen, uroporphyrinogen III, protoporphyrin IX, and finally heme upon chelation with iron. Porphyrin metabolism is related to chromoproteins like hemoglobin, methemoglobin, sulfhemoglobin, carboxyhemoglobin, metalbumin, and myoglobin which contain heme and transport or store oxygen in vertebrates and some
This document provides information on heme synthesis and disorders of heme synthesis (porphyrias). It describes the 7 step process of heme biosynthesis, which takes place partly in the cytoplasm and mitochondria. The key steps involve the formation of porphobilinogen (PBG), uroporphyrinogen, coproporphyrinogen, protoporphyrinogen, and finally heme through the insertion of iron. Regulation and some specific porphyrias are also outlined, including acute intermittent porphyria, congenital erythropoietic porphyria, porphyria cutanea tarda, hereditary coproporphyria, and variegate porphyria.
Heme Biosynthesis and Its disorders (Porphyria)Ashok Katta
Hemoglobin is a protein in red blood cells that transports oxygen and carbon dioxide throughout the body. It is made up of four subunits, each containing a heme group with iron at its center. Heme biosynthesis is a multi-step pathway that takes place in the mitochondria and cytoplasm, starting from succinyl-CoA and glycine and resulting in protoporphyrin with iron inserted at the final step to form heme. Regulation of heme biosynthesis occurs through feedback inhibition of the rate-limiting enzyme ALA synthase by heme levels. Deficiencies in the heme biosynthesis pathway can cause various types of porphyrias, a group of rare genetic disorders characterized by neurological and skin abnormalities.
Biosynthesis and degradation of porphyrin and hemesountharya Sen s
This document summarizes the biosynthesis and degradation of porphyrin and heme. It discusses how glycine and succinyl CoA are condensed to form δ-aminolevulinate, the starting material for porphyrin synthesis. Four molecules of porphobilinogen then condense to form the porphyrin ring. A series of reactions incorporates iron to form heme. Heme is degraded through heme oxygenase to form biliverdin and bilirubin, which is transported to the liver bound to albumin.
Content :-
What is porphyrin?
Biosynthesis of porphyrin (heme)
Site
Reactions
Regulation
Degradation of heme
Site
Reactions
Reference
What is Porphyrin?
Porphyrins are cyclic compound formed by the linkage of four pyrrole rings through methyne(=HC-)bridges.
Structure of hemoglobin & chlorophyll
Examples of some important humanand animal hemoproteins.
Biosynthesis of heme
Site of biosynthesis:-
-Liver (hepatocyte) & Bone Marrow
( erythryoid producing cells )
2) ALA dehydratase :-
The substrates are two molecules of ALA.
The product is porphobilinogen, the first pyrrole.
ALA dehydratase is a -SH containing enzyme.
It is very susceptible to inhibition by lead.
3) Uroporphyrinogen I synthase and uroporphyrinogen IIIcosynthase
Production of uroporphyrinogen III requires two enzymes.The substrates are four molecules of porphobilinogen.
4) Uroporphyrinogen decarboxylase:-
Decarboxylates the acetic acid groups, converting them to methyl groups.
5) Coproporphyrinogen III oxidase:-
Catalyzes the conversion of two propionic acid groups to vinyl groups
6) Protoporphyrinogen IX oxidase:-
Protoporphyrinogen IX oxidase converts the methylene bridges between the pyrrole rings to methenyl bridges.
7) Ferrochelatase:-
Ferrochelatase adds Fe++ to protoporphyrin IX, forming heme.
• The enzyme requires Fe++, ascorbic acid and cysteine (reducing agents).
• Ferrochelatase is inhibited by lead.
Regulation of heme synthesis
Feedback regulation:- heme is a feedback inhibitor of ALA synthase. ALA synthase occurs in both hepatic (ALAS 1) and erythroid (ALAS 2) forms.
Effects of drugs and steroids:- Certain drugs and steroids can increase heme synthesis via increased production of the ratelimiting enzyme, ALA synthase
Substrate availability:- Fe++ must be available for ferrochelatase.
Degradation of heme
Site of Degradation :-
- cells of the reticulo endothelial system in spleen, liver and bone marrow
Heme Degradation
Most of the heme which is degraded comes from hemoglobin in red blood cells, which have a life span of about 120 days.
There is thus a turnover of about 6 g/day of hemoglobin.
Normally , senescent red blood cells and heme from other sources are engulfed by cells of the reticuloendothelial system.
The globin is recycled or converted into amino acids, which in turn are recycled or catabolized as required.
Heme is oxidized.
Microsomal heme oxygenase system
Transport of bilirubin in Plasma
Bilirubin on release from macrophages circulates as unconjugated bilirubin in plasma tightly bound to albumin.
HARPER’S ILLUSTRATED BIOCHEMISTRY (28TH EDITION) by robert murray,david A.bender,peter j kennekky,victor w rodwell,p.antony weil.(page No-271)
Biochemistry Lippincott’s Illustrated Reviews by Richard Harvey& Denise Ferrier
Porphyrins are cyclic compounds that bind metal ions and are central to important biological processes like oxygen transport and utilization. Heme, the most prevalent metalloporphyrin in humans, is synthesized through a multi-step pathway where two building blocks are condensed and modified to eventually form protoporphyrin IX, which chelates iron to become heme. Disorders can occur if enzymes in the heme synthesis pathway are deficient, leading to toxic accumulation of intermediates and causing the group of diseases called porphyrias.
Heme is an important porphyrin compound primarily synthesized in the liver and bone marrow. Heme synthesis begins with glycine and succinyl CoA condensing to form δ-aminolevulinate in mitochondria, a rate-controlling step. Two δ-aminolevulinate molecules then condense to form porphobilinogen. Four porphobilinogen molecules condense and interact with enzymes to form the porphyrin ring and later uroporphyrinogen III. Further enzymatic conversions form protoporphyrin IX, and iron is incorporated via ferrochelatase to finally synthesize heme. Heme synthesis is regulated differently in the liver versus bone marrow cells.
This document summarizes key information about heme chemistry and hemoglobin. It discusses the structure and function of hemoglobin, including its role in oxygen transport and delivery to tissues. Hemoglobin is a protein composed of globin and heme groups that allows for the reversible binding and transport of oxygen in the blood. Factors like pH, carbon dioxide levels, and cooperativity between heme groups influence the oxygen binding affinity of hemoglobin.
Biosynthesis of Purine Ribonucleotide, GoutAshok Katta
This document summarizes purine nucleotide synthesis pathways. It discusses two main pathways: de novo synthesis and salvage pathway. De novo synthesis involves assembling the purine ring from various precursors on ribose-5-phosphate. The salvage pathway recycles purine bases and nucleosides obtained from dietary sources or nucleic acid degradation. The committed step in de novo synthesis is controlled by the concentration of PRPP, which depends on the availability of ribose-5-phosphate and the activity of PRPP synthase.
This document summarizes the de novo synthesis of pyrimidine nucleotides. It describes the precursors and reactions involved in synthesizing the pyrimidine ring and then attaching it to ribose phosphate to form the pyrimidine nucleotides CMP, UMP and TMP. It also discusses the conversion of UDP to CTP and dTMP, the regulation of pyrimidine synthesis, salvage pathways, catabolism of pyrimidines, and the genetic disorder orotic aciduria caused by a defect in the enzyme UMP synthase.
Transamination and the urea cycle are two key metabolic pathways for processing amino acids in the body. Transamination allows for the interconversion of amino acids and intermediates in carbohydrate metabolism pathways. The urea cycle processes excess nitrogen produced during amino acid catabolism into urea for excretion. Phenylketonuria is a disorder caused by mutations that decrease the metabolism of phenylalanine. This can lead to toxic buildup of phenylalanine and associated neurological impairments if left untreated with a phenylalanine-restricted diet and nutritional supplements. Alkaptonuria is another inborn error of amino acid metabolism resulting from a deficiency in homogentisate oxidase that causes discoloration of
BIOSYNTHESIS OF NUCLEOTIDE COENZYMES AND THEIR ROLE IN METABOLISMNaba Kalita
Nucleotide coenzymes are compounds that contain a simple nucleotide moiety and function in association with specific apoenzymes or proteins. Historically, the first nucleotide coenzyme discovered was diphosphopyridine nucleotide or cozymase. Nucleotide coenzymes like NAD+, NADP+, FAD, FMN, CoA, and PAPS play important roles in metabolism as electron carriers and substrates for enzymatic reactions involved in oxidation-reduction, biosynthesis, and other metabolic pathways. Their biosynthesis involves the attachment of nucleotides like AMP to organic molecules through phosphorylation or other reactions.
Heme synthesis occurs partly in the cytosol and partly in the mitochondria of erythroid precursor cells and liver cells. The 8 step process involves the formation of delta-aminolevulinic acid from succinyl CoA and glycine, which then condenses and cyclizes through intermediates like porphobilinogen, hydroxymethylbilane and uroporphyrinogen to finally form protoporphyrin. In the last step, iron is incorporated by the enzyme ferrochelatase to produce heme. Deficiencies in the enzymes involved at different steps can lead to various types of porphyrias.
This document summarizes several disorders associated with amino acid metabolism, including albinism, alkaptonuria, and phenylketonuria. Albinism is caused by a lack of melanin pigment due to defects in the tyrosinase enzyme. Alkaptonuria is caused by a defect in the enzyme homogentisate 1,2-dioxygenase, leading to a buildup of homogentisic acid and the darkening of cartilage and urine. Phenylketonuria results from a defect in the enzyme phenylalanine hydroxylase, causing an accumulation of phenylalanine that can lead to intellectual disabilities if left untreated.
This document discusses the metabolism of fructose and galactose. It outlines the dietary sources and absorption pathways of each sugar. Fructose is metabolized separately in the liver and muscle, while galactose is metabolized through a pathway involving phosphorylation, reduction, and synthesis of UDP-galactose. The document also describes inborn errors that can occur in these metabolic pathways, including fructokinase deficiency, aldolase B deficiency, and classic galactosemia due to galactose-1-phosphate uridylyltransferase deficiency. These errors can result in conditions like fructosuria, fructose intolerance, and galactosemia.
Hemoglobin is an oxygen-binding protein in red blood cells. It is composed of four polypeptide subunits - two alpha chains and two beta chains - as well as a heme group containing iron. The heme group gives hemoglobin its red color and allows it to carry oxygen from the lungs to tissues and carbon dioxide from tissues back to the lungs. Mutations in hemoglobin genes can lead to hemoglobinopathies like thalassemias, sickle cell anemia, and hemoglobin M disease. These disorders disrupt hemoglobin's ability to carry oxygen and can cause anemia.
Lactate dehydrogenase (LDH) is an enzyme that catalyzes the conversion of lactate to pyruvate. It exists as five isoenzymes (LDH-1 to LDH-5) that differ in their subunit composition and electric charge. The isoenzymes show varying tissue distribution, catalytic properties, and clinical significance. Elevated levels of specific isoenzymes can help identify the origin of tissue damage, as LDH-1 and LDH-2 indicate myocardial infarction while LDH-4 and LDH-5 signify liver damage. The LDH isoenzyme pattern also provides information about different cancer types.
Phenylalanine is converted to tyrosine by the enzyme phenylalanine hydroxylase in the liver. Tyrosine can then be incorporated into proteins or converted to important compounds like melanin, thyroid hormones, dopamine, norepinephrine, and epinephrine. The metabolism of phenylalanine and tyrosine involves multiple enzymatic steps and requires cofactors like biopterin, ascorbic acid, and molecular oxygen. Disorders in these pathways can lead to conditions like albinism or Parkinson's disease.
Describes the different pathways involved in the synthesis of different eicosanoids like prostaglandins, leukotrienes, lipoxins etc along with different enzymes involved.
Heme is an important prosthetic group found in hemoglobin, myoglobin, and cytochromes. It is synthesized through a pathway involving 8 enzymes, with deficiencies leading to various porphyrias. The acute hepatic porphyrias involve deficiencies in enzymes from the middle of the pathway, resulting in accumulation of aminolevulinic acid and porphobilinogen that can cause severe abdominal pain, neuropathy, and psychiatric symptoms. Diagnosis involves urine and stool tests showing elevated levels of pathway intermediates. Treatment focuses on managing acute attacks and avoiding precipitating factors.
Porphyrias are metabolic disorders of heme synthesis characterized by increased excretion of porphyrins or their precursors. There are two main types - hepatic, where the enzyme defect is in the liver, and erythropoietic, where it is in bone marrow. Some specific types include acute intermittent porphyria, porphyria cutanea tarda, hereditary coproporphyria, and variegate porphyria. Symptoms vary but can include abdominal pain, photosensitivity, and neuropsychiatric issues. Treatment depends on the specific type but may involve inhibiting certain enzymes to reduce accumulation of intermediates.
This document discusses photosynthesis and cellular respiration. It outlines the key pigments involved in photosynthesis like chlorophyll a and b as well as carotenoids. It also describes the light and dark reactions of photosynthesis, including the cyclic and non-cyclic pathways. For cellular respiration, it distinguishes between aerobic and anaerobic respiration, listing lactic acid fermentation and alcoholic fermentation as types of anaerobic respiration. It further breaks down aerobic respiration into the preparatory, oxidative, and pyruvic acid oxidation phases and describes the citric acid cycle and respiratory chain.
The document discusses amino acid metabolism. It begins by outlining the major pathways of amino acid metabolism, including transamination, deamination, and decarboxylation. These pathways allow amino acids to be used for protein synthesis, energy production, and the formation of other nitrogenous compounds. The urea cycle is also summarized, which involves several steps to produce urea from ammonia in the liver. Finally, some specific amino acids like glycine are discussed in more detail regarding their catabolism. In general, the carbon skeletons of amino acids enter central metabolic pathways while the amino groups are removed as ammonia and ultimately excreted as urea.
The document summarizes the hexose monophosphate pathway (HMP pathway), also known as the pentose phosphate pathway. It has three main functions: 1) supply NADPH, 2) convert hexoses to pentoses, and 3) enable complete oxidation of pentoses. NADPH functions as an electron donor in biosynthetic reactions, unlike NADH which generates ATP. The pathway occurs in the cytosol and is important in tissues that synthesize fatty acids and steroids, as it provides the required NADPH. Glucose utilization via this pathway varies between tissues and is higher in liver, adipose tissue, and erythrocytes. Deficiencies in enzymes in this pathway can cause
This document discusses various types of porphyrias, which are inherited disorders of heme biosynthesis that can cause neurological or cutaneous symptoms. It describes the symptoms and causes of specific types such as acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), porphyria cutanea tarda (PCT), and erythropoietic prophyrias. It also covers the diagnostic testing and treatment approaches for different porphyrias based on the underlying enzyme deficiency and clinical manifestations.
1) Amino acids can be converted into specialized nitrogen-containing compounds like porphyrins, neurotransmitters, hormones, purines and pyrimidines.
2) Porphyrins are cyclic molecules that readily bind metal ions like iron. The most common metalloporphyrin in humans is heme, which is essential for hemoglobin and other hemeproteins.
3) Heme is synthesized through a multi-step pathway starting with the condensation of glycine and succinyl-CoA to form delta-aminolevulinic acid (ALA) in the liver and bone marrow. Defects in this pathway result in the rare inherited disorder known as porphyria.
The document discusses heme metabolism and catabolism. It describes how heme is synthesized through a series of steps starting with glycine and succinyl CoA and ending with the addition of iron to protoporphyrin. Heme contains an iron atom bound to a protoporphyrin ring and functions as a prosthetic group in hemoglobin, myoglobin, cytochromes and other proteins. The catabolism of heme yields bilirubin which is conjugated and excreted in bile. Disorders can occur if there are defects in heme synthesis or catabolism.
Porphyrins are cyclic compounds that bind metal ions and are central to important biological processes like oxygen transport and utilization. Heme, the most prevalent metalloporphyrin in humans, is synthesized through a multi-step pathway where two building blocks are condensed and modified to eventually form protoporphyrin IX, which chelates iron to become heme. Disorders can occur if enzymes in the heme synthesis pathway are deficient, leading to toxic accumulation of intermediates and causing the group of diseases called porphyrias.
Heme is an important porphyrin compound primarily synthesized in the liver and bone marrow. Heme synthesis begins with glycine and succinyl CoA condensing to form δ-aminolevulinate in mitochondria, a rate-controlling step. Two δ-aminolevulinate molecules then condense to form porphobilinogen. Four porphobilinogen molecules condense and interact with enzymes to form the porphyrin ring and later uroporphyrinogen III. Further enzymatic conversions form protoporphyrin IX, and iron is incorporated via ferrochelatase to finally synthesize heme. Heme synthesis is regulated differently in the liver versus bone marrow cells.
This document summarizes key information about heme chemistry and hemoglobin. It discusses the structure and function of hemoglobin, including its role in oxygen transport and delivery to tissues. Hemoglobin is a protein composed of globin and heme groups that allows for the reversible binding and transport of oxygen in the blood. Factors like pH, carbon dioxide levels, and cooperativity between heme groups influence the oxygen binding affinity of hemoglobin.
Biosynthesis of Purine Ribonucleotide, GoutAshok Katta
This document summarizes purine nucleotide synthesis pathways. It discusses two main pathways: de novo synthesis and salvage pathway. De novo synthesis involves assembling the purine ring from various precursors on ribose-5-phosphate. The salvage pathway recycles purine bases and nucleosides obtained from dietary sources or nucleic acid degradation. The committed step in de novo synthesis is controlled by the concentration of PRPP, which depends on the availability of ribose-5-phosphate and the activity of PRPP synthase.
This document summarizes the de novo synthesis of pyrimidine nucleotides. It describes the precursors and reactions involved in synthesizing the pyrimidine ring and then attaching it to ribose phosphate to form the pyrimidine nucleotides CMP, UMP and TMP. It also discusses the conversion of UDP to CTP and dTMP, the regulation of pyrimidine synthesis, salvage pathways, catabolism of pyrimidines, and the genetic disorder orotic aciduria caused by a defect in the enzyme UMP synthase.
Transamination and the urea cycle are two key metabolic pathways for processing amino acids in the body. Transamination allows for the interconversion of amino acids and intermediates in carbohydrate metabolism pathways. The urea cycle processes excess nitrogen produced during amino acid catabolism into urea for excretion. Phenylketonuria is a disorder caused by mutations that decrease the metabolism of phenylalanine. This can lead to toxic buildup of phenylalanine and associated neurological impairments if left untreated with a phenylalanine-restricted diet and nutritional supplements. Alkaptonuria is another inborn error of amino acid metabolism resulting from a deficiency in homogentisate oxidase that causes discoloration of
BIOSYNTHESIS OF NUCLEOTIDE COENZYMES AND THEIR ROLE IN METABOLISMNaba Kalita
Nucleotide coenzymes are compounds that contain a simple nucleotide moiety and function in association with specific apoenzymes or proteins. Historically, the first nucleotide coenzyme discovered was diphosphopyridine nucleotide or cozymase. Nucleotide coenzymes like NAD+, NADP+, FAD, FMN, CoA, and PAPS play important roles in metabolism as electron carriers and substrates for enzymatic reactions involved in oxidation-reduction, biosynthesis, and other metabolic pathways. Their biosynthesis involves the attachment of nucleotides like AMP to organic molecules through phosphorylation or other reactions.
Heme synthesis occurs partly in the cytosol and partly in the mitochondria of erythroid precursor cells and liver cells. The 8 step process involves the formation of delta-aminolevulinic acid from succinyl CoA and glycine, which then condenses and cyclizes through intermediates like porphobilinogen, hydroxymethylbilane and uroporphyrinogen to finally form protoporphyrin. In the last step, iron is incorporated by the enzyme ferrochelatase to produce heme. Deficiencies in the enzymes involved at different steps can lead to various types of porphyrias.
This document summarizes several disorders associated with amino acid metabolism, including albinism, alkaptonuria, and phenylketonuria. Albinism is caused by a lack of melanin pigment due to defects in the tyrosinase enzyme. Alkaptonuria is caused by a defect in the enzyme homogentisate 1,2-dioxygenase, leading to a buildup of homogentisic acid and the darkening of cartilage and urine. Phenylketonuria results from a defect in the enzyme phenylalanine hydroxylase, causing an accumulation of phenylalanine that can lead to intellectual disabilities if left untreated.
This document discusses the metabolism of fructose and galactose. It outlines the dietary sources and absorption pathways of each sugar. Fructose is metabolized separately in the liver and muscle, while galactose is metabolized through a pathway involving phosphorylation, reduction, and synthesis of UDP-galactose. The document also describes inborn errors that can occur in these metabolic pathways, including fructokinase deficiency, aldolase B deficiency, and classic galactosemia due to galactose-1-phosphate uridylyltransferase deficiency. These errors can result in conditions like fructosuria, fructose intolerance, and galactosemia.
Hemoglobin is an oxygen-binding protein in red blood cells. It is composed of four polypeptide subunits - two alpha chains and two beta chains - as well as a heme group containing iron. The heme group gives hemoglobin its red color and allows it to carry oxygen from the lungs to tissues and carbon dioxide from tissues back to the lungs. Mutations in hemoglobin genes can lead to hemoglobinopathies like thalassemias, sickle cell anemia, and hemoglobin M disease. These disorders disrupt hemoglobin's ability to carry oxygen and can cause anemia.
Lactate dehydrogenase (LDH) is an enzyme that catalyzes the conversion of lactate to pyruvate. It exists as five isoenzymes (LDH-1 to LDH-5) that differ in their subunit composition and electric charge. The isoenzymes show varying tissue distribution, catalytic properties, and clinical significance. Elevated levels of specific isoenzymes can help identify the origin of tissue damage, as LDH-1 and LDH-2 indicate myocardial infarction while LDH-4 and LDH-5 signify liver damage. The LDH isoenzyme pattern also provides information about different cancer types.
Phenylalanine is converted to tyrosine by the enzyme phenylalanine hydroxylase in the liver. Tyrosine can then be incorporated into proteins or converted to important compounds like melanin, thyroid hormones, dopamine, norepinephrine, and epinephrine. The metabolism of phenylalanine and tyrosine involves multiple enzymatic steps and requires cofactors like biopterin, ascorbic acid, and molecular oxygen. Disorders in these pathways can lead to conditions like albinism or Parkinson's disease.
Describes the different pathways involved in the synthesis of different eicosanoids like prostaglandins, leukotrienes, lipoxins etc along with different enzymes involved.
Heme is an important prosthetic group found in hemoglobin, myoglobin, and cytochromes. It is synthesized through a pathway involving 8 enzymes, with deficiencies leading to various porphyrias. The acute hepatic porphyrias involve deficiencies in enzymes from the middle of the pathway, resulting in accumulation of aminolevulinic acid and porphobilinogen that can cause severe abdominal pain, neuropathy, and psychiatric symptoms. Diagnosis involves urine and stool tests showing elevated levels of pathway intermediates. Treatment focuses on managing acute attacks and avoiding precipitating factors.
Porphyrias are metabolic disorders of heme synthesis characterized by increased excretion of porphyrins or their precursors. There are two main types - hepatic, where the enzyme defect is in the liver, and erythropoietic, where it is in bone marrow. Some specific types include acute intermittent porphyria, porphyria cutanea tarda, hereditary coproporphyria, and variegate porphyria. Symptoms vary but can include abdominal pain, photosensitivity, and neuropsychiatric issues. Treatment depends on the specific type but may involve inhibiting certain enzymes to reduce accumulation of intermediates.
This document discusses photosynthesis and cellular respiration. It outlines the key pigments involved in photosynthesis like chlorophyll a and b as well as carotenoids. It also describes the light and dark reactions of photosynthesis, including the cyclic and non-cyclic pathways. For cellular respiration, it distinguishes between aerobic and anaerobic respiration, listing lactic acid fermentation and alcoholic fermentation as types of anaerobic respiration. It further breaks down aerobic respiration into the preparatory, oxidative, and pyruvic acid oxidation phases and describes the citric acid cycle and respiratory chain.
The document discusses amino acid metabolism. It begins by outlining the major pathways of amino acid metabolism, including transamination, deamination, and decarboxylation. These pathways allow amino acids to be used for protein synthesis, energy production, and the formation of other nitrogenous compounds. The urea cycle is also summarized, which involves several steps to produce urea from ammonia in the liver. Finally, some specific amino acids like glycine are discussed in more detail regarding their catabolism. In general, the carbon skeletons of amino acids enter central metabolic pathways while the amino groups are removed as ammonia and ultimately excreted as urea.
The document summarizes the hexose monophosphate pathway (HMP pathway), also known as the pentose phosphate pathway. It has three main functions: 1) supply NADPH, 2) convert hexoses to pentoses, and 3) enable complete oxidation of pentoses. NADPH functions as an electron donor in biosynthetic reactions, unlike NADH which generates ATP. The pathway occurs in the cytosol and is important in tissues that synthesize fatty acids and steroids, as it provides the required NADPH. Glucose utilization via this pathway varies between tissues and is higher in liver, adipose tissue, and erythrocytes. Deficiencies in enzymes in this pathway can cause
This document discusses various types of porphyrias, which are inherited disorders of heme biosynthesis that can cause neurological or cutaneous symptoms. It describes the symptoms and causes of specific types such as acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), porphyria cutanea tarda (PCT), and erythropoietic prophyrias. It also covers the diagnostic testing and treatment approaches for different porphyrias based on the underlying enzyme deficiency and clinical manifestations.
1) Amino acids can be converted into specialized nitrogen-containing compounds like porphyrins, neurotransmitters, hormones, purines and pyrimidines.
2) Porphyrins are cyclic molecules that readily bind metal ions like iron. The most common metalloporphyrin in humans is heme, which is essential for hemoglobin and other hemeproteins.
3) Heme is synthesized through a multi-step pathway starting with the condensation of glycine and succinyl-CoA to form delta-aminolevulinic acid (ALA) in the liver and bone marrow. Defects in this pathway result in the rare inherited disorder known as porphyria.
The document discusses heme metabolism and catabolism. It describes how heme is synthesized through a series of steps starting with glycine and succinyl CoA and ending with the addition of iron to protoporphyrin. Heme contains an iron atom bound to a protoporphyrin ring and functions as a prosthetic group in hemoglobin, myoglobin, cytochromes and other proteins. The catabolism of heme yields bilirubin which is conjugated and excreted in bile. Disorders can occur if there are defects in heme synthesis or catabolism.
Porphyrin metabolism involves the biosynthesis of heme through a series of enzymatic reactions in the liver and erythroid tissues. Deficiencies in enzymes involved in this pathway can result in porphyrias, characterized by accumulation of porphyrin intermediates and excessive porphyrin excretion in urine, sometimes with neurovisceral symptoms. Heme is degraded through the action of heme oxygenase to form biliverdin and ultimately bilirubin, which is conjugated and excreted in bile and urine. Elevated bilirubin levels can cause jaundice through various mechanisms of liver dysfunction or increased heme breakdown.
This document provides information about heme metabolism and porphyrias. It begins with the structure of porphyrins and important heme proteins. It then describes the 8 steps of heme biosynthesis, which occur partly in mitochondria and partly in cytosol. The rate-limiting step is the conversion of glycine and succinyl-CoA to delta-aminolevulinic acid (ALA) by ALA synthase. The document also discusses the regulation of heme synthesis and disorders of heme synthesis called porphyrias, which result from defects in heme biosynthesis.
- Heme metabolism involves the synthesis of heme from glycine and succinyl-CoA in the mitochondria and cytoplasm, as well as the degradation of heme to bilirubin in the spleen and liver.
- Regulation of heme synthesis differs between the liver and erythroid cells. Various genetic disorders can arise from deficiencies in heme synthesis enzymes, leading to toxic accumulations of intermediates and porphyrias.
- Hyperbilirubinemia and different types of jaundice can occur due to imbalances in bilirubin production, conjugation, or excretion, and may relate to hemolytic anemia, liver dysfunction, or biliary obstruction.
billirubin production billirubin transport and metabolism, different laboratory methods of billirubin estimation ,normal and abnormal levels of billirubin, different classification and types of jaundice and liver diseses, liver functioning, enterohepatic circulation, billirubin production and degradation, benefits and diseases of abnormal level of billirubin
This document provides information on bilirubin, including its structure, formation, transport, conjugation, and excretion. It discusses how bilirubin is formed through the breakdown of heme in macrophages and hepatic cells. Unconjugated bilirubin is transported to the liver bound to albumin and taken up by hepatocytes. In hepatocytes, bilirubin is conjugated with glucuronic acid and excreted into bile. The conjugated bilirubin passes through the intestines where it is broken down by bacteria before being excreted.
This document discusses heme metabolism and porphyrias. It begins by describing the structures and functions of hemoglobin and myoglobin. It then covers the steps of heme biosynthesis, from porphobilinogen to heme. Factors affecting hemoglobin synthesis are also outlined. The document discusses various porphyrias caused by defects in heme biosynthesis enzymes. The clinical manifestations of different porphyrias are attributed to the accumulation of toxic intermediates upstream of the genetic block.
This document provides information on porphyrins, their chemistry, metabolism, biosynthesis, and degradation. It discusses how porphyrins bind metallic ions like iron to form metalloporphyrins. The biosynthesis of porphyrins occurs in multiple steps in both the mitochondria and cytosol of liver and red blood cells. Porphyrins are degraded in the spleen, liver, and bone marrow. The document also covers the regulation, clinical features, applications, and conclusions regarding porphyrins and heme synthesis and metabolism.
1. Haem is synthesized through 8 enzymatic steps involving 8 molecules of succinyl CoA and glycine.
2. The pathway involves both cytosolic and mitochondrial enzymes with the rate-limiting step being ALA synthase which is inhibited by haem and glucose.
3. Deficiencies in the enzymes can lead to various porphyrias like acute intermittent porphyria or erythropoietic protoporphyria.
Heme is an essential molecule found in hemoglobin, myoglobin, and various enzymes. The document discusses heme synthesis, porphyrias which result from defects in heme synthesis, and the classification and inheritance of different types of porphyrias. It provides details on each step of heme synthesis, the enzymes involved, and which intermediates accumulate in different porphyria types causing symptoms like photosensitivity or neurological issues.
Thia is an elaborate study of the metabolism of amino acids and proteins.
This will help you to understand the different stages and steps involved in metabolism.
The document discusses bilirubin, including its formation from the breakdown of heme, transport via albumin in plasma, uptake and conjugation in the liver, excretion in bile, and role as a diagnostic marker for liver and blood disorders. Methods for measuring total and direct bilirubin are also presented, based on the reaction of bilirubin with diazotized sulphanilic acid to form colored azobilirubin derivatives.
1. Heme synthesis occurs in mitochondria and involves two starting molecules, succinyl CoA and glycine. The reaction produces aminolevulonic acid and needs the enzyme ALA synthase.
2. There are several types of hemoglobin in humans including HbA, HbA2, fetal Hb, and HbA1c. HbA1c levels are used to monitor diabetes by indicating average blood glucose levels over several weeks.
3. Abnormal hemoglobins include methemoglobin, carboxyhemoglobin, sulfhemoglobin, and hematin. Porphyrias are diseases caused by deficiencies in heme synthesis enzymes that can cause anemia, pain, and photosensitivity.
This document summarizes heme metabolism and porphyrias. It discusses that heme is an iron-containing porphyrin that serves as a prosthetic group in hemoglobin and other proteins. Heme is synthesized through a three step process from glycine and succinyl-CoA. The first step involving ALA synthase is regulated by a feedback mechanism with heme. Disorders of heme synthesis can be genetic or acquired, such as lead poisoning disrupting the pathway. Porphyrias are a group of inherited disorders resulting from deficiencies in heme synthesis enzymes, causing accumulation of porphyrin precursors and symptoms like abdominal pain or neuropsychiatric issues.
This document discusses porphyrias, which are rare inherited or acquired defects in heme synthesis that result in the accumulation and increased excretion of porphyrins or porphyrin precursors. It describes different types of porphyrias including chronic hepatic porphyria, acute hepatic porphyrias, and erythropoietic porphyrias. It also discusses the degradation of heme during erythrocyte destruction and the formation and elimination of bilirubin, as well as different types of jaundice including hemolytic, hepatocellular, and obstructive jaundice. Special consideration is given to jaundice in newborns.
This document provides information on liver function tests. It begins with an overview of liver anatomy and functions including synthesis, metabolism, and excretion. It then discusses specific tests that evaluate these hepatic functions and their clinical implications. Details are provided on liver zonation and regeneration. Key proteins and enzymes synthesized by the liver are outlined. Metabolic functions like ammonia, carbohydrate, and xenobiotic metabolism are reviewed. Inherited disorders of bilirubin metabolism that can cause jaundice are also summarized.
Heme metabolism involves the synthesis of heme in the liver from glycine and succinyl-CoA. Heme consists of an iron atom within a porphyrin ring structure and is involved in oxygen transport as part of hemoglobin. Heme synthesis is regulated by feedback inhibition from heme itself and stimulation by drugs like phenobarbital. Excess heme is broken down to bilirubin in the liver, conjugated with glucuronic acid and excreted in bile or blood. Hyperbilirubinemia can be prehepatic from hemolysis, hepatic from liver disease, or posthepatic from bile duct obstruction. The type and location of bilirubin increase and changes in urine/
1. Hemoglobin and other heme-containing proteins are broken down, releasing iron and producing bilirubin, which is conjugated in the liver and excreted in bile and feces.
2. Heme synthesis takes place in the liver and bone marrow and is regulated by negative feedback inhibition by heme.
3. Issues with heme metabolism can cause porphyrias or jaundice in newborns from immature bilirubin conjugation enzymes.
This document discusses the chemistry of proteins. It begins by classifying proteins and their functions in organisms. It then discusses the structure and properties of amino acids, including their classification based on structure, polarity, nutrition requirements, and metabolic fate. It introduces peptides and peptide bonds. Key points are that proteins are composed of amino acids joined by peptide bonds, there are 20 standard amino acids, and proteins serve important structural and dynamic roles in organisms.
This document provides information on carbohydrates including their definition, classification, structures, and biological importance. It begins by defining carbohydrates and discussing their classification into monosaccharides, oligosaccharides, and polysaccharides based on the number of sugar units. Important monosaccharides like glucose, fructose, and galactose are described along with their reactions and structural aspects. Disaccharides such as sucrose, lactose, and maltose are also discussed. The document then covers polysaccharides including starch, glycogen, and mucopolysaccharides; and concludes by emphasizing the key roles and functions of carbohydrates in biological systems.
Vitamins and minerals are essential nutrients that humans must obtain through their diet. There are two classes of vitamins - fat soluble (A, D, E, K) and water soluble. Fat soluble vitamins are absorbed with fat and can accumulate in the body, while water soluble vitamins are not readily stored. Vitamins function as coenzymes and precursors for important metabolic processes. Deficiencies can lead to diseases like rickets, osteomalacia and night blindness. Common dietary sources of vitamins and requirements are also discussed.
This document summarizes key aspects of genetics, including the structure and function of DNA, RNA, and their role in replication, transcription, and translation. It describes the primary, secondary, and tertiary structures of DNA and different types of RNA, including their structure and role in protein synthesis. Specifically, it notes that DNA stores and transmits genetic information as sequences of nucleotides, while various RNAs (mRNA, tRNA, rRNA) are involved in transcription and translation using this genetic code to produce proteins.
This document discusses nucleotides and their metabolism. It begins by defining nucleotides and their roles in biochemical processes as the monomeric units of DNA and RNA. It then describes how purine and pyrimidine nucleotides differ based on their nitrogenous base and pentose residue, and how DNA contains deoxyribonucleotides while RNA contains ribonucleotides. The document goes on to explain that inosine monophosphate is the initially synthesized purine derivative, and that AMP and GMP are subsequently synthesized from this intermediate via separate pathways. It concludes by outlining the first step in pyrimidine ring synthesis and the synthesis of thymine from dUMP.
This document summarizes the metabolic roles of major organs including the liver, muscle, adipose tissue, and brain. It also discusses the hormonal regulators of fuel metabolism including insulin, glucagon, and catecholamines. Insulin promotes anabolic processes like glycogen, lipid, and protein synthesis. Glucagon and catecholamines have opposing catabolic effects and stimulate glycogenolysis, gluconeogenesis and lipolysis. Together these hormones maintain blood glucose levels and allow fuels to be distributed and used by different tissues.
This document discusses lipid metabolism. It covers the digestion and absorption of lipids in the small intestine through the actions of lingual lipase, gastric lipase, pancreatic lipase, and bile salts. It also discusses the transportation of lipids through the lymphatic system via chylomicrons. Fatty acids are oxidized through beta-oxidation in the liver to produce acetyl-CoA and ketone bodies as an energy source, especially during fasting. Fat-soluble vitamins are absorbed with lipids and transported in the blood and lymph within lipoproteins and chylomicrons.
Water is the most abundant constituent of cells and plays a critical role in biochemical reactions. It has unique physical and chemical properties due to its dipolar structure and ability to form hydrogen bonds between molecules. These hydrogen bonds allow water to solvate a wide range of molecules and influence their structure. Water also acts as a reactant and product in many metabolic reactions and helps maintain pH balance in the body. Disruptions to water balance can cause health issues.
Protein digestion begins with pepsin and HCL in the stomach breaking proteins into smaller peptides. In the small intestine, pancreatic proteases including trypsin further break peptides into amino acids. Amino acids are actively absorbed into intestinal cells via sodium-coupled amino acid transporters and released into the bloodstream. Excess amino acid nitrogen from dietary and cellular proteins is converted to ammonia in tissues then transported to the liver. In the liver, ammonia is incorporated into urea through the urea cycle and excreted in urine.
This document provides an overview of carbohydrate chemistry. It defines carbohydrates and discusses their biological importance and classification. Key points include: carbohydrates are composed of carbon, hydrogen, and oxygen and serve important energy storage and structural functions. They are classified as monosaccharides, oligosaccharides, or polysaccharides based on the number of sugar units. Common monosaccharides include glucose, fructose, galactose and mannose. Disaccharides like lactose, maltose and sucrose are formed via glycosidic bonds between monosaccharides. Polysaccharides have high molecular weights and include starch, glycogen and mucopolysaccharides.
This document discusses DNA structure and replication. It begins by describing the structure of DNA as a double helix with two antiparallel strands held together by hydrogen bonds between complementary nucleotide base pairs. DNA replication is then summarized as a semi-conservative process where the parental DNA strands separate and each acts as a template for new complementary strands to be synthesized, resulting in two new DNA molecules each with one original and one new strand. The key steps of replication including initiation, unwinding of the strands, primer formation, elongation of new strands, and ligation are also outlined.
This document summarizes biologically important nucleotides and their functions. It discusses the composition of nucleotides and their roles in DNA, RNA, and various biochemical functions. Specific nucleotides are described, including adenosine nucleotides (ATP, ADP, AMP, cAMP), guanosine nucleotides (GTP, GDP, GMP, cGMP), uridine nucleotides (UTP, UDP, UMP, UDP-G), and cytidine nucleotides (CTP, CDP, CMP). It also discusses purine and pyrimidine metabolism, including biosynthesis, degradation, salvage pathways, and disorders like hyperuricemia, gout, and Lesch-Nyhan syndrome. The regulation and enzymes involved in
1. The document discusses carbohydrate metabolism, including glycolysis, the citric acid cycle (TCA cycle), gluconeogenesis, glycogenesis, and glycogenolysis.
2. Glycolysis converts glucose to pyruvate, producing ATP and NADH. The TCA cycle further oxidizes pyruvate, producing more ATP, NADH, and FADH2.
3. Gluconeogenesis produces glucose from non-carbohydrate sources. Glycogenesis and glycogenolysis involve the synthesis and breakdown of glycogen for glucose storage and mobilization.
This document discusses carbohydrate chemistry, metabolism, and regulation. It covers:
- The structure and classification of carbohydrates including monosaccharides, disaccharides, oligosaccharides, and polysaccharides.
- The digestion of carbohydrates in the mouth, stomach, and small intestine by enzymes that break down polysaccharides and oligosaccharides into monosaccharides like glucose, which are then absorbed.
- The metabolism of glucose through three main pathways: glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation to generate cellular energy. Glycolysis occurs anaerobically in the cytosol and aerobically in the mitochondria.
- The regulation of blood glucose levels through pathways
This document summarizes important enzymes and lipoproteins that are investigated in cases of cardiac diseases. It discusses several serum enzymes that are elevated during a myocardial infarction (MI), including creatine kinase, aspartate transaminase, lactate dehydrogenase, and troponins. It provides details on what tissues they are found in, when levels peak after an MI, and their diagnostic value. It also discusses lipoproteins like LDL, HDL, and lipoprotein(a) and their relationships to cardiovascular health. Specifically, elevated LDL is viewed as harmful while elevated HDL is beneficial due to its role in removing cholesterol from tissues. High levels of lipoprotein(a) are also an independent risk factor as it can inhibit fibrinolysis and promote
1. Gene expression can be regulated positively or negatively at the levels of transcription, RNA processing, translation and protein activity through the actions of regulatory proteins and hormones.
2. Hormones like steroids enter cells and bind nuclear receptors to activate transcription, while peptide hormones signal through cell surface receptors and secondary messengers.
3. Key mechanisms of transcriptional control include chromatin remodeling, DNA methylation, and the binding of transcription factors to regulatory sequences which can either promote or block transcription initiation.
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Strategies for Effective Upskilling is a presentation by Chinwendu Peace in a Your Skill Boost Masterclass organisation by the Excellence Foundation for South Sudan on 08th and 09th June 2024 from 1 PM to 3 PM on each day.
it describes the bony anatomy including the femoral head , acetabulum, labrum . also discusses the capsule , ligaments . muscle that act on the hip joint and the range of motion are outlined. factors affecting hip joint stability and weight transmission through the joint are summarized.
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This presentation includes basic of PCOS their pathology and treatment and also Ayurveda correlation of PCOS and Ayurvedic line of treatment mentioned in classics.
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Biological screening of herbal drugs: Introduction and Need for
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2. A description on the synthesis of
porphyrin and heme
Porphyrins are cyclic compounds that readily
bind metal ions—usually Fe2+ or Fe3+. The
most prevalent metalloporphyrin in humans is
heme, which consists of one ferrous (Fe2+) iron
ion coordinated in the center of the tetrapyrrole
ring of proto porphyrin IX.
Heme is the prosthetic group for hemoglobin,
myoglobin, the cytochromes, catalase, nitric
oxide synthase, and peroxidase.
3. • These hemeproteins are rapidly synthesized
and degraded. For example, 6–7 g of
hemoglobin are synthesized each day to
replace heme lost through the normal
turnover of erythrocytes.
• Coordinated with the turnover of
hemeproteins is the simultaneous synthesis
and degradation of the associated
porphyrins, and recycling of the bound iron
ions.
4. Structure of porphyrins
• Porphyrins are cyclic molecules formed by
the linkage of four pyrrole rings through
methenyl bridges (Figure 21.2). Three
structural features of these molecules are
relevant to understanding their medical
significance.
5.
6.
7.
8.
9. Biosynthesis of heme
The major sites of heme biosynthesis are the
liver, which synthesizes a number of heme
proteins (particularly cytochrome P450
proteins), and the erythrocyte-producing cells of
the bone marrow, which are active in
hemoglobin synthesis.
• In the liver, the rate of heme synthesis is
highly variable, responding to alterations in
the cellular heme pool caused by fluctuating
demands for heme proteins.
10. • In contrast, heme synthesis in erythroid cells
is relatively constant, and is matched to the
rate of globin synthesis. The initial reaction
and the last three steps in the formation of
porphyrins occur in mitochondria, whereas
the intermediate steps of the biosynthetic
pathway occur in the cytosol.
11. 1. Formation of δ-aminolevulinic acid (ALA):
All the carbon and nitrogen atoms of the
porphyrin molecule are provided by glycine (a
nonessential amino acid) and Succinyl
coenzyme A (an intermediate in the citric acid
cycle) that condense to form ALA in a reaction
catalyzed by ALA synthase (ALAS) (Figure
21.3) This reaction requires pyridoxal
phosphate (PLP) as a coenzyme, and is the
committed and rate-limiting step in porphyrin
biosynthesis
12.
13. • 2. Formation of porphobilinogen: The
condensation of two molecules of ALA to
form porphobilinogen by Zn-containing
ALA dehydratase (porphobilinogen
synthase) is extremely sensitive to inhibition
by heavy metal ions, for example, lead that
replace the zinc (see Figure 21.3). This
inhibition is, in part, responsible for the
elevation in ALA and the anemia seen in
lead poisoning.
14.
15. 3. Formation of uroporphyrinogen: The
condensation of four porpho bilinogens
produces the linear tetrapyrrole,
hydroxymethyl - bilane, which is isomerized
and cyclized by uroporphyrinogen III
synthase to produce the asymmetric
uroporphyrinogen III. This cyclic tetrapyrrole
undergoes decarboxylation of its acetate
groups, generating coproporphyrinogen III
(Figure 21.4). These reactions occur in the
cytosol.
16.
17. 4. Formation of heme: Coproporphyrinogen
III enters the mitochondrion, and two
propionate side chains are decarboxylated to
vinyl groups generating protoporphyrinogen
IX, which is oxidized to protoporphyrin IX.
The introduction of iron (as Fe2+) into
protoporphyrin IX occurs spontaneously, but
the rate is enhanced by ferro - chelatase, an
enzyme that, like ALA dehydratase, is
inhibited by lead (Figure 21.5).
18.
19.
20.
21.
22.
23. Catabolism of Heme and Formation of
Bilirubin
After approximately 120 days in the
circulation, red blood cells are taken up and
degraded by the reticuloendothelial system,
particularly in the liver and spleen (Figure
21.9). Approximately 85% of heme destined for
degradation comes from senescent red blood
cells, and 15% is from turnover of immature
red blood cells and cytochromes from
nonerythroid tissues.
24. • 1. Formation of bilirubin: The first step in the
degradation of heme is catalyzed by the
microsomal heme oxygenase system of the
reticuloendothelial cells. In the presence of
NADPH and O2, the enzyme adds a hydroxyl
group to the methenyl bridge between two
pyrrole rings, with a concomitant oxidation of
ferrous iron to Fe3+. A second oxidation by the
same enzyme system results in cleavage of the
porphyrin ring. The green pigment biliverdin is
produced as ferric iron and CO are released (see
Figure 21.9). Biliverdin is reduced, forming the
red-orange bilirubin. Bilirubin and its derivatives
are collectively termed bile pigments.
25.
26. • 2. Uptake of bilirubin by the liver: Bilirubin is
only slightly soluble in plasma and, therefore, is
transported to the liver by binding
noncovalently to albumin. [Note: Certain
anionic drugs, such as salicylates and
sulfonamides, can displace bilirubin from
albumin, permitting bilirubin to enter the central
nervous system. This causes the potential for
neural damage in infants.] Bilirubin dissociates
from the carrier albumin molecule, enters a
hepatocyte via facilitated diffusion, and binds to
intracellular proteins, particularly the protein
ligandin.
27.
28. • 3. Formation of bilirubin diglucuronide: In the
hepatocyte, the solubility of bilirubin is
increased by the addition of two molecules of
glucuronic acid. [Note: This process is referred
to as conjugation.]
• The reaction is catalyzed by microsomal
bilirubin glucuronyl - transferase using uridine
diphosphate-glucuronic acid as the glucuronate
donor. [Note: Varying degrees of deficiency of
this enzyme result in Crigler-Najjar I and II and
Gilbert syndrome, with Crigler-Najjar I being
the most severe deficiency.]
29.
30. • 4. Secretion of bilirubin into bile: Bilirubin
diglucuronide (conjugated bilirubin) is actively
transported against a concentration gradient
into the bile canaliculi and then into the bile.
This energy-dependent, rate-limiting step is
susceptible to impairment in liver disease.
• [Note: A deficiency in the protein required for
transport of conjugated bilirubin out of the liver
results in Dubin-Johnson syndrome.]
Unconjugated bilirubin is normally not
secreted.
31.
32. • 5. Formation of urobilins in the intestine:
Bilirubin diglucuronide is hydrolyzed and
reduced by bacteria in the gut to yield
urobilinogen, a colorless compound. Most of
the urobilinogen is oxidized by intestinal
bacteria to stercobilin, which gives faeces the
characteristic brown color. However, some of
the urobilinogen is reabsorbed from the gut
and enters the portal blood.
33. • A portion of this urobilinogen participates in
the enterohepatic urobilinogen cycle in which
it is taken up by the liver, and then resecreted
into the bile. The remainder of the
urobilinogen is transported by the blood to
the kidney, where it is converted to yellow
urobilin and excreted, giving urine its
characteristic color.
34.
35. Clinical Correlates
A. Porphyrias
• Porphyrias are rare, inherited (or occasionally
acquired) defects in heme synthesis, resulting
in the accumulation and increased excretion of
porphyrins or porphyrin precursors. [Note:
With few exceptions, porphyrias are inherited
as autosomal dominant disorders.] The
mutations that cause the porphyrias are
heterogenous (not all are at the same DNA
locus), and nearly every affected family has its
own mutation.
36. • Each porphyria results in the accumulation
of a unique pattern of intermediates caused
by the deficiency of an enzyme in the heme
synthetic pathway.
37. Clinical manifestations:
• The porphyrias are classified as erythropoietic
or hepatic, depending on whether the enzyme
deficiency occurs in the erythropoietic cells of
the bone marrow or in the liver.
• Hepatic porphyrias can be further classified as
chronic or acute. In general, individuals with
an enzyme defect prior to the synthesis of the
tetrapyrroles manifest abdominal and neuro
psychiatric signs, whereas those with enzyme
defects leading to the accumulation of
tetrapyrrole intermediates show
photosensitivity— that is, their skin itches and
burns (pruritus) when exposed to visible light.
38. • a. Chronic hepatic porphyria: Porphyria
cutanea tarda, the most common porphyria,
is a chronic disease of the liver. The disease
is associated with a deficiency in uro
porphyrinogen decarboxylase, but clinical
expression of the enzyme deficiency is
influenced by various factors, such as hepatic
iron overload, exposure to sunlight, alcohol
ingestion, and the presence of hepatitis B or
C, or HIV infections.
39. • Clinical onset is typically during the fourth
or fifth decade of life. Porphyrin
accumulation leads to cutaneous symptoms
(Figure 21.6), and urine that is red to brown
in natural light (Figure 21.7), and pink to red
in fluorescent light.
40. • b. Acute hepatic porphyrias: Acute hepatic
porphyrias (ALA dehydratase deficiency,
acute intermittent porphyria, hereditary
coproporphyria, and variegate porphyria)
are characterized by acute attacks of gastro
intestinal, neuro psychiatric, and motor
symptoms that may be accompanied by
photosensitivity.
41. • Porphyrias leading to accumulation of ALA
and porphobilinogen, such as acute
intermittent porphyria, cause abdominal pain
and neuro psychiatric disturbances, ranging
from anxiety to delirium.
42. c. Erythropoietic porphyrias: The
erythropoietic porphyrias (congenital
erythropoietic porphyria and erythropoietic
protoporphyria) are characterized by skin
rashes and blisters that appear in early
childhood. The diseases are complicated by
cholestatic liver cirrhosis and progressive
hepatic failure.
43. B. Jaundice
Jaundice (also called icterus) refers to the yellow
color of skin, nail beds, and sclerae (whites of the eyes)
caused by deposition of bilirubin, secondary to
increased bilirubin levels in the blood
(hyperbilirubinemia. Although not a disease, jaundice
is usually a symptom of an underlying disorder.
• Types of jaundice: Jaundice can be classified into
three major forms described below. However, in
clinical practice, jaundice is often more complex than
indicated in this simple classification.
• For example, the accumulation of bilirubin may be a
result of defects at more than one step in its
metabolism.
44. • a. Hemolytic jaundice: The liver has the
capacity to conjugate and excrete over 3,000 mg
of bilirubin per day, whereas the normal
production of bilirubin is only 300 mg/day.
This excess capacity allows the liver to respond
to increased heme degradation with a
corresponding increase in conjugation and
secretion of bilirubin diglucuronide. However,
massive lysis of red blood cells (for example, in
patients with sickle cell anemia, pyruvate kinase
or glucose 6-phosphate dehydrogenase
deficiency) may produce bilirubin faster than it
can be conjugated.
45. • Unconjugated bilirubin levels in the blood
become elevated, causing jaundice. [Note:
More conjugated bilirubin is excreted into
the bile, the amount of urobilinogen entering
the enterohepatic circulation is increased,
and urinary urobilinogen is increased.]
46.
47. b. Hepatocellular jaundice: Damage to liver
cells (for example, in patients with cirrhosis or
hepatitis) can cause unconjugated bilirubin
levels in the blood to increase as a result of
decreased conjugation. Urobilinogen is
increased in the urine because hepatic damage
decreases the enterohepatic circulation of this
compound, allowing more to enter the blood,
from which it is filtered into the urine.
48. • The urine thus darkens, whereas stools may
be a pale, clay color. Plasma levels of AST
and ALT are elevated. [Note: If conjugated
bilirubin is not efficiently secreted from the
liver into bile (intrahepatic cholestasis), it can
diffuse (“leak”) into the blood, causing a
conjugated hyperbilirubinemia.]
49. • c. Obstructive jaundice: In this instance,
jaundice is not caused by overproduction of
bilirubin or decreased conjugation, but
instead results from obstruction of the bile
duct (extrahepatic cholestasis). For example,
the presence of a tumor or bile stones may
block the bile ducts, preventing passage of
bilirubin into the intestine. Patients with
obstructive jaundice experience
gastrointestinal pain and nausea, and
produce stools that are a pale, clay color, and
urine that darkens upon standing.
50. • The liver “regurgitates” conjugated bilirubin
into the blood (hyperbilirubinemia). The
compound is eventually excreted in the
urine. Urinary urobiloinogen is absent.
[Note: Pro longed obstruction of the bile duct
can lead to liver damage and a subsequent
rise in unconjugated bilirubin.]
51.
52.
53. • Jaundice in newborns: Newborn infants,
particularly if premature, often accumulate bilirubin,
because the activity of hepatic bilirubin
glucuronyltransferase is low at birth—it reaches
adult levels in about 4 weeks. Elevated bilirubin, in
excess of the binding capacity of albumin, can
diffuse into the basal ganglia and cause toxic
encephalopathy (kernicterus).
• Thus, newborns with significantly elevated bilirubin
levels are treated with blue fluorescent light, which
converts bilirubin to more polar and, hence, water-
soluble isomers. These photoisomers can be excreted
into the bile without conjugation to glucuronic acid.