A compele text of heme synthesis and the diseases associated with the process. Diseases have been discussed under the points of clinical featues, lab findings and treatment.
This presentation deals with the various aspects of porphyria and their biochemical basis. Their investigation algorithms and flowchart. This also deals with clinical symptoms and their management. The presentation uses a lot of flowcharts so that it's easier to follow.
This presentation deals with the various aspects of porphyria and their biochemical basis. Their investigation algorithms and flowchart. This also deals with clinical symptoms and their management. The presentation uses a lot of flowcharts so that it's easier to follow.
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
Heme Catabolism and Degradation Pathway #Bilirubin metabolismAHLAD T.O
This video is about heme catabolism or heme degradation. Heme is degraded into bilirubin in a heme degradation pathway. Heme degradation pathway or heme degradation biochemistry is important for understanding different types of bilirubin being elevated in jaundice. Types of jaundice can be classified based on the type of bilirubin being elevated in the blood. Heme catabolism or heme degradation is important concept
Heme Catabolism (Heme Degradation Pathway)
heme catabolism
Bilirubin metabolism ( Heme catabolism)
Heme Catabolism and Degradation Pathway - Biochemistry Lesson
Bilirubin metabolism
Heme catabolism
Heme catabolism || Bilirubin metabolism || #Biochemistry
steps
Introduction
Bilirubin formation pathway
Transport of bilirubin to liver
Uptake of bilirubin in liver
Conjugation of bilirubin
Excretion of bilirubin in bile canaliculi
Fate of conjugated bilirubin in intestine
Entero-hepatic circulation of urobilinogen
Final excretion of UBG and SBG
As the channel name suggests, our channel will be a perfect lounge for the malayali medicos..we wil be covering videos which will be like lecture classes related to the subjects biochemistry and microbiology in which we are specialised.. It will be a better learning experience for the students especially for those who are not able to understand and follow the normal classes in college..we assure the students that you will get a basic idea regarding the topic and extra reading can be done from the reference textbooks...
If you like my video
#like
#comment
#subscribe my channel
don't forget to subscribe my channel
Qualification
Ahlad.T.O
MSc MLT (Biochemistry)
Assistant Professor
Baby memorial college of allied Health science
Kozhikode
Our Partner Channel
Health & Voyage channel link - https://youtu.be/nzKqRVjlwc0
Heme catabolism
Heme degradation in macrophages
Bilirubin transport with albumin
Bilirubin metabolism
1. Uptake by hepatocytes by facilitated diffusion
2. Conjugation of unconjugated bilirubin
3. Secretion in to bile canaliculi by active transport through MRP 2
Congenital causes
UNCONJUGATED BILIRUBIN INCREASE
1. Crigler Najjar type 1
2. Crigler Najjar type 2
3. Gilbert syndrome
Conjugated bilirubin increase
1. Dubin Johnson syndrome
2. Rotor syndrome
#Mallu
#Microbiology
#Biochemistry
#MalluMedicosLounge
#HealthAndVoyage
#How to take online class
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
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.
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
Heme Catabolism and Degradation Pathway #Bilirubin metabolismAHLAD T.O
This video is about heme catabolism or heme degradation. Heme is degraded into bilirubin in a heme degradation pathway. Heme degradation pathway or heme degradation biochemistry is important for understanding different types of bilirubin being elevated in jaundice. Types of jaundice can be classified based on the type of bilirubin being elevated in the blood. Heme catabolism or heme degradation is important concept
Heme Catabolism (Heme Degradation Pathway)
heme catabolism
Bilirubin metabolism ( Heme catabolism)
Heme Catabolism and Degradation Pathway - Biochemistry Lesson
Bilirubin metabolism
Heme catabolism
Heme catabolism || Bilirubin metabolism || #Biochemistry
steps
Introduction
Bilirubin formation pathway
Transport of bilirubin to liver
Uptake of bilirubin in liver
Conjugation of bilirubin
Excretion of bilirubin in bile canaliculi
Fate of conjugated bilirubin in intestine
Entero-hepatic circulation of urobilinogen
Final excretion of UBG and SBG
As the channel name suggests, our channel will be a perfect lounge for the malayali medicos..we wil be covering videos which will be like lecture classes related to the subjects biochemistry and microbiology in which we are specialised.. It will be a better learning experience for the students especially for those who are not able to understand and follow the normal classes in college..we assure the students that you will get a basic idea regarding the topic and extra reading can be done from the reference textbooks...
If you like my video
#like
#comment
#subscribe my channel
don't forget to subscribe my channel
Qualification
Ahlad.T.O
MSc MLT (Biochemistry)
Assistant Professor
Baby memorial college of allied Health science
Kozhikode
Our Partner Channel
Health & Voyage channel link - https://youtu.be/nzKqRVjlwc0
Heme catabolism
Heme degradation in macrophages
Bilirubin transport with albumin
Bilirubin metabolism
1. Uptake by hepatocytes by facilitated diffusion
2. Conjugation of unconjugated bilirubin
3. Secretion in to bile canaliculi by active transport through MRP 2
Congenital causes
UNCONJUGATED BILIRUBIN INCREASE
1. Crigler Najjar type 1
2. Crigler Najjar type 2
3. Gilbert syndrome
Conjugated bilirubin increase
1. Dubin Johnson syndrome
2. Rotor syndrome
#Mallu
#Microbiology
#Biochemistry
#MalluMedicosLounge
#HealthAndVoyage
#How to take online class
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
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.
PORPHYRIA, a metabolic disorder of heme-biosynthesis enzyme which leads to accumulation of porphyrins & its precursors with wide range prevalence and manifestations. Slides have brief details of disease with its classification, diagnostic algorithms chart, images to simplify observation, treatment & management etc.
Details of integration of metabolism of three main food content - Carbs, fat and proteins in the form of flow chart - easy to understand and easy to remember.
This powerpoint contains details regarding detoxication reactions of xenobiotics. Examples of reactions of different phases of detoxication has been given.
A brief discussion on cytochrome P450 is also included.
A concise note for undergraduate students to learn the use of isotopes in research, analytical and treatment purpose in modern medicine. It also contains the basic of radioactivity and the health hazards associated with it.
Quality control, or QC for short, is a process by which entities review the quality of all factors involved in the production. ISO 9000 defines quality control as "A part of quality management focused on fulfilling quality requirements"
This presentation gives a brief idea of Quality control and how to execute it.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
2. STRUCTURE OF HEME
- Conjugated protein
- Derivative of porphyrin
- Cyclic compounds formed by fusion of 4 pyrrole rings
- Linked by methenyl (=CH-) bridges
3. • The pyrrole rings are named as I, II, III, IV
• The bridges as alpha, beta, gamma and delta
• The possible areas of substitution are denoted as 1 to 8
4.
5. BIOSYNTHESIS OF PORPHYRINS:
SITES:
Partly mitochondria, partly cytoplasm (developing erythrocytes and
hepatic cells
STAGES:
Stage I: Synthesis of δ - ALA - in mitochondria
Stage II: Synthesis of coproporphyrinogen III (major series) and
coproporphyrinogen I (minor series) - in cytosol
Stage III: Synthesis of protoporphyrin IX – in mitochondria
6. Stage I: Synthesis of δ - ALA
• Condensation of ‘succinyl CoA’ (“active” succinate) and glycine
• Form ‘α-amino-β-Ketoadipic acid”.
• α-amino-β-ketoadipic acid undergoes decarboxylation to produce
δ-ALA
7. δ-ALA Synthetase Enzyme and its Regulation
• Erythropoietic substances including stimulate haem synthesis by
inducing the production of the enzyme
• End product ‘haem’ inhibits the enzyme by “feedback” inhibition
• Haem causes a repression of the synthesis of the enzyme
8. Stage II: Synthesis of coproporphyrinogen III and I
1. Formation of Porphobilinogen –
• Two molecules of δ-ALA condense to form a molecule of
porphobilinogen
• Catalysed by δ-ALA dehydratase (Zn Containing enzyme), Cu
as a cofactor
• Inhibited by lead
9. 2. Formation of Uroporphyrinogen I and III
• 4 mol. of porphobilinogens condense, losing 4 mol. of NH3
• Forms uroporphyrinogen I (minor series)
• Enzyme responsible porphobilinogen deaminase or
uroporphyrinogen-I synthetase
10. • Reversal of one porphobilinogen residue form uroporphyrinogen III
• Enzyme - an isomerase: uroporphyrinogen III cosynthetase
• In IVth pyrrole ring, acetic acid and propionic acid side chains are
“reversed” (cf. uroporphyrinogen I)
11. 3. Formation of
Coproporphyrinogen I
and III
• Four acetic acid side
chains get
decarboxylated
• Form methyl groups
• Enzyme–
Uroporphyrinogen
decarboxylase
12. Stage III: Formation of Protoporphyrin IX
• An oxidative decarboxylase system converts coproporphyrinogen
III to protoporphyrinogen IX
• Flavin acts as co-enzyme
• Protoporphyrinogen IX is converted to protoporphyrin IX another
oxidase enzyme
• The above steps require the presence of molecular O2
13.
14. Formation of Haem and Haemoproteins
• Insertion of an atom of Fe++ into central position of protoporphyrin
IX
• Catalysed by haem synthetase (ferrochelatase)
• Requirement:
– Anaerobiosis
– Reducing agents such as glutathione
15.
16. Regulation of Heme synthesis:
1. Effect of O2
- In vivo: Stimulated by low O2 tension
- In vitro: Conversion of porphobilinogen to uroporphyrinogen and
protoporphyrin to haem - inhibited by O2
- Decarboxylation of coproporphyrinogen – promoted by O2
2. Drugs: Many compound cause increase in hepatic δ-ALA
synthetase, leading to increased porphyrins
3. Hypoxia: increases δ-ALA synthetase activity
4. Steroids: drug meditated ‘derepression’ of δ-ALA synthetase
5. Iron: induction of δ-ALA synthetase.
17. 6. Enzyme Inhibition: Haem, the end-product of the metabolic
sequence, inhibits the activity of synthetase.
7. Lead: Inhibits δ-ALA synthetase, δ-ALA dehydratase and haem
synthetase
8. Glucose: Prevent induction of δ-ALA synthetase
9. Haematin: prevent the drug-mediated ‘derepression’ of δ-ALA
synthetase.
18. PORPHYRIAS
When the blood levels of coproporphyrins and uroporphyrins are
increased above normal level and excreted in urine/faeces, the
condition is called porphyria
19.
20. I. Hereditary (Inherited) Porphyrias
A. Congenital Erythropoietic Porphyrias
Site of Lesion
- Expressed in erythropoietic tissues and affects red bone marrow
Inheritance
- Autosomal recessive
Enzyme Deficiency
- Deficiency of isomerase enzyme
21. Clinically
- Photosensitivity and skin lesions
- Porphyrins accumulate under the skin, normoblasts and erythrocytes.
- Teeth and bones may be brownish or pink due to porphyrin
deposition
Biochemically
- Increased amounts of porphyrins of type I
Urinary findings
- Portwine’ or ‘red’ coloured urine
- Contains type I isomers, oxidised to uroporphyrin I and
coproporphyrin I
22. Mast cell activation by complement activation induced by
protoporphyrin and irradiation
Release of preformed mediators from mast cells
Causes erythema, edema, and urticaria
Interaction of mast cells with fibroblasts, along with protoporphyrin
and irradiation contribute to the waxy thickening of skin
23. B. Hepatic porphyrias
a) Intermittent acute porphyria (IAP)
- Known as Paroxysmal porphyria
Inheritance:
Autosomal dominant
Enzyme deficiency:
Partial deficiency of deaminase (uroporphyrinogen I synthetase),
expressed in hepatic cells only
Race:
Found in Swedish family
24. Clinical features:
- GI symptoms
- CV abnormalities and neuropsychiatric signs and symptoms.
- Photosensitivity absent
- Increase in serum protein bound iodine
- Hypercholesterolaemia and diabetic type of Glucose tolerance curve
Urinary findings:
- On standing in sunlight urine turns to red wine colour.
- Increased quantities of porphobilinogen and δ-ALA
Biochemically: There is always associated catalase deficiency
25. b) Porphyria Cutanea Tarda
Race:
South African whites
Inheritance:
- Autosomal dominant
- Associated with hepatic injury, particularly alcohol or iron overload
Enzyme deficiency:
Partial deficiency of uroporphyrinogen decarboxylase
Clinical features:
Characterised principally by skin photosensitivity
26. Photoactivation of the complement and presence of uroporphyrin results in
activation of dermal mast cells
Results in dermal-epidermal separation, clinically as skin fragility and
vesicles
Uroporphyrin stimulates collagen biosynthesis by fibroblasts (independent
of irradiation)
Sclerodermoid lesions seen at sun-exposed as well as sun-protected areas
28. (c) Variegate Porphyria
Mixed or combined type porphyria
Inheritance:
Autosomal dominant.
Enzyme deficiency:
Partial block of enzymatic conversion of protoporphyrin IX to haem
Enzymes deficiency:
• Protoporphyrinogen oxidase, and
• Ferrochelatase (haemsynthetase)
29. Clinical features:
Mixed presentation.
Acute attacks of pain in abdomen, nausea and vomiting, constipation
Neuropsychiatric signs and symptoms
Cutaneous photosensitivity
Urinary findings:
Excretes δ-ALA, porphobilinogen and type I and III isomers
30. II. Acquired Porphyrias
a. Coproporphyrin type III
- Exposure to certain toxic chemicals and heavy metals
- Acute alcoholism
- Cirrhosis of the liver
- Conditions like poliomyelitis, aplastic anaemia, Hodgkin’s disease.
b. Coproporphyrin type I:
Abnormally large quantities of coproporphyrin type I found in the urine
- Obstructive jaundice
- Cirrhosis in non-alcoholics
- Haemolytic anaemia, pernicious anaemia and leukaemias.
31. Fluorescence of Porphyrins:
- Porphyrins dissolved in strong mineral acids or in organic solvents
- Illuminated by UV light
- Emit a strong red fluorescence
- The fluorescence is characteristic of free porphyrins.
The double bonds joining the pyrrole rings in the porphyrins are
responsible for the characteristic absorption and fluorescence of
these compounds
32. Cancer Phototherapy:
- Tumours often take up more porphyrins than do normal tissues
- Haematoporphyrins or other related compounds are administered to
a patient with appropriate tumour
- The tumour is then exposed to an argon laser, which excites the
porphyrins producing cytotoxic effects
33. 1. Which of the following steps in the biosynthesis of porphyrins is the
rate-controlling?
a. Uroporphyrinogen I synthetase
b. Uroporphyrinogen decarboxylase
c. δ-amino laevulinate synthetase
d. Protoporphyrinogen oxidase
e. None of the above
2. Substrates required for haemoglobin biosynthesis are:
a. ‘Active acetate’ and glycine
b. Glycine and ‘formate’
c. ‘Active succinate’ and lysine
d. ‘Active succinate and glycine
e. Formate and lysine
34. 3. Which of the porphyrins go into the formation of protoporphyrin IX?
a. Type I series b. Type II series
c. Type III series d. None of the above
e. All of the above
4. In the biosynthesis of porphyrins, which of the coenzyme is required for
δ-ALA formation:
a. FAD b. NAD+
c. NADP+ d. B6 – PO4
e. FMN
35. 5. δ-ALA dehydratase enzyme requires for its activity:
a. Fe++ b. Cu++
c. Mn d. Co
e. Mg
6. Oxidative decarboxylase system which converts coproporphyrinogen
III to protoporphyrinogen IX requires
which of the coenzyme:
a. NAD+ b. B6 – PO4
c. TPP d. Flavins
e. CoA-S
36. 7. The enzyme which catalyses the synthesis of Haem from
protoporphyrin IX is:
a. Ferroreductase b. Ferrochelatase
c. Ferro oxidase d. None of the above
e. All of the above
8. In mammalian liver, conversion of coproporphyrinogen III to
protoporphyrinogen IX requires the presence of:
a. ATP b. Molecular oxygen
c. Mg++ d. B6 – (P)
e. NAD+
37. 9. Uroporphyrin and coproporphyrin of which series is excreted in
urine in congenital erythropoietic porphyria:
a. Type I series b. Type II series
c. Type III series d. None of the above
e. All of the above
Editor's Notes
two forms of ALAS. ALAS1 is considered a housekeeping gene and is expressed in all cells. ALAS2 is an erythroidspecific form of the enzyme and is expressed only in fetal liver and adult bone marrow. The ALAS1 gene is located on chromosome 3, whereas the ALAS2 gene is located on the X chromosome. Deficiencies in ALAS2 result in a disorder called X-linked sideroblastic anemia, XLSA
In which the acetic acid and propionic acid side chains alternate.
diminishes the cellular concentration of haem, leading to ‘derepression’ of δ-ALA synthetase
acute attacks of abdominal pain, nausea and vomiting, constipation;
neurological manifestations like sensory and motor disturbances, confusion and agitation.
increased production of porphobilinogen and δ-ALA
Exposure to air, polymerises to form two coloured red compounds porphobilin and porphyrin
acute attacks of abdominal pain, nausea and vomiting, constipation;
neurological manifestations like sensory and motor disturbances, confusion and agitation.
increased production of porphobilinogen and δ-ALA
Exposure to air, polymerises to form two coloured red compounds porphobilin and porphyrin
Explanation: Relative haem deficiency produced under
stressful conditions leads to derepression of hepatic δ-ALA
synthetase, which results in increased activity of δ-ALA
synthetase leading to overproduction of all the intermediates
of haem synthesis (precursors over production).
The double bonds are absent in the porphyrinogens hence they do not give fluorescence