Amino acids are broken down through various pathways into seven main metabolic intermediates: pyruvate, α-ketoglutarate, succinyl-CoA, fumarate, oxaloacetate, acetyl-CoA, or acetoacetate. The amino acids can be categorized as either glucogenic or ketogenic based on which intermediate they are degraded into. Alanine, cysteine, glycine, serine, and threonine are degraded into pyruvate through transamination or reactions involving the cofactor pyridoxal phosphate. Arginine, glutamate, glutamine, histidine, and proline are degraded into α-ketoglutarate through conversion to glutamate
De novo and salvage pathway of nucleotides synthesis.pptx✨M.A kawish Ⓜ️
This slides explains Metabolism topic "De novo and salvage pathway of nucleotides synthesis. In which synthesis of Purines and pyrimidines synthesis has been occurred. In last there is a difference between these two pathways.
Digestion of proteins, absorption of amino acids, synthesis of amino acids, catabolism of amino acids and synthesis of specialised non-protein compounds from amino acids for undergraduates
De novo and salvage pathway of nucleotides synthesis.pptx✨M.A kawish Ⓜ️
This slides explains Metabolism topic "De novo and salvage pathway of nucleotides synthesis. In which synthesis of Purines and pyrimidines synthesis has been occurred. In last there is a difference between these two pathways.
Digestion of proteins, absorption of amino acids, synthesis of amino acids, catabolism of amino acids and synthesis of specialised non-protein compounds from amino acids for undergraduates
This PPT is on Amino acid metabolism. And the topics covered under this ppt are Transamination, deamination
Book referred: https://www.amazon.in/Biochemistry-2019-Satyanarayana-Satyanarayana-Author/dp/B07WGHCTKZ/ref=sr_1_1?dchild=1&qid=1591608419&refinements=p_27%3AU+Satyanarayana&s=books&sr=1-1
introduction of Purine and Pyrimidine metabolism, biosynthesis and degradation of nucleotides, biological functions and metabolic disorders, chemical analogues and therapeutic drugs, uric acid metabolism
Nucleotide metabolism (purine and pyrimidine synthesis)Areeba Ghayas
NUCLEOTIDE METABOLISM,DE NOVO SYNTHESIS OF PURINE, SALVAGE PATHWAY OF PURINE, DE-NOVO SYNTHESIS OF PYRIMIDINE, SALVAGE PATHWAY OF PYRIMIDINE, GOUT, HYPERURICEMIA, LESCH-NYAN SYNDROME, OROTIC ACIDURIA
Substrate level phosphorylation and it's mechanism || Biochemistry || B Pharmacy || Project || slideshare || biology || chemistry
*images use in this ppt is only for educational purpose
In this presentation, i tell about substrate level phosphorylation
Phosphorylation involves the transfer of phosphate
group from one compound to other.
➢ Substrate level phosphorylation is a direct
phosphorylation of ADP with a phosphatase group by
using the energy obtain from a coupled reaction.
➢ Occurs in cytoplasm ( glycolysis – due to aerobic and
anaerobic condition) and in mitochondrial matrix ( krebs
cycle – anaerobic condition)
This PPT is on Amino acid metabolism. And the topics covered under this ppt are Transamination, deamination
Book referred: https://www.amazon.in/Biochemistry-2019-Satyanarayana-Satyanarayana-Author/dp/B07WGHCTKZ/ref=sr_1_1?dchild=1&qid=1591608419&refinements=p_27%3AU+Satyanarayana&s=books&sr=1-1
introduction of Purine and Pyrimidine metabolism, biosynthesis and degradation of nucleotides, biological functions and metabolic disorders, chemical analogues and therapeutic drugs, uric acid metabolism
Nucleotide metabolism (purine and pyrimidine synthesis)Areeba Ghayas
NUCLEOTIDE METABOLISM,DE NOVO SYNTHESIS OF PURINE, SALVAGE PATHWAY OF PURINE, DE-NOVO SYNTHESIS OF PYRIMIDINE, SALVAGE PATHWAY OF PYRIMIDINE, GOUT, HYPERURICEMIA, LESCH-NYAN SYNDROME, OROTIC ACIDURIA
Substrate level phosphorylation and it's mechanism || Biochemistry || B Pharmacy || Project || slideshare || biology || chemistry
*images use in this ppt is only for educational purpose
In this presentation, i tell about substrate level phosphorylation
Phosphorylation involves the transfer of phosphate
group from one compound to other.
➢ Substrate level phosphorylation is a direct
phosphorylation of ADP with a phosphatase group by
using the energy obtain from a coupled reaction.
➢ Occurs in cytoplasm ( glycolysis – due to aerobic and
anaerobic condition) and in mitochondrial matrix ( krebs
cycle – anaerobic condition)
Fate of Glucogenic and Ketogenic amino acid
Amino acid are the currency of of nitrogen and protein economy of the host, hence they are used in many pathways beyond protein synthesis, including energy production and neurotransmitter synthesis.
All amino acid are comprised of an amino group and a carbon skeleton. During metabolism these two parts are separated as they have different ‘fates’
Of the liberated amino acid approximately 75% are utilized while remainder serve as precursors for important biological compound and those not utilized are degraded to amphibolic intermediates
The pathway of amino acid catabolism is quite similar in most organism
Methionine metabolism
Activation of methionine and transmethylation
Conversion of methionine to cysteine
Degradation of cysteine.
Cysteine metabolism
Formation
Metabolic Function
Metabolism Disorders of Sulfur containing amino acid
Fates of Amino Acids
🠶 Amino Acid Utilization
🠶 Amino-group metabolism
🠶 Explain role of transamination reactions in aa synthesis and identify vitamin essential for this reaction (tie in to urea cycle)
🠶 Describe interconversion between ketoacids and AA, including requirement of
pyridoxal phosphate (PLP) as a cofactor
🠶 Outline formation and transport of ammonia
🠶 Describe importance of reactions catalyzed by glutamine synthetase, glutaminase, and glutamate dehydrogenase
🠶 Ammonia Intoxication
🠶List causes for hyperammonemia, its consequences, and treatments to reduce blood ammonia levels
citric acid cycle or TCA cycle.
krebs cycle is amphibolic in nature and its important reactions.
occurs in mitochondrial matrix in close proximity to ETC.
5 types of vitamins are involved in this cycle. also inhibitors are present . regulation of TCA cycle is governed by mainly 3 enzymes
and there is mention the energies of every step that takes place in citric acid cycle.
citric acid cycle produces 24 molecules of ATP in every cycle
Welcome to TechSoup New Member Orientation and Q&A (May 2024).pdfTechSoup
In this webinar you will learn how your organization can access TechSoup's wide variety of product discount and donation programs. From hardware to software, we'll give you a tour of the tools available to help your nonprofit with productivity, collaboration, financial management, donor tracking, security, and more.
June 3, 2024 Anti-Semitism Letter Sent to MIT President Kornbluth and MIT Cor...Levi Shapiro
Letter from the Congress of the United States regarding Anti-Semitism sent June 3rd to MIT President Sally Kornbluth, MIT Corp Chair, Mark Gorenberg
Dear Dr. Kornbluth and Mr. Gorenberg,
The US House of Representatives is deeply concerned by ongoing and pervasive acts of antisemitic
harassment and intimidation at the Massachusetts Institute of Technology (MIT). Failing to act decisively to ensure a safe learning environment for all students would be a grave dereliction of your responsibilities as President of MIT and Chair of the MIT Corporation.
This Congress will not stand idly by and allow an environment hostile to Jewish students to persist. The House believes that your institution is in violation of Title VI of the Civil Rights Act, and the inability or
unwillingness to rectify this violation through action requires accountability.
Postsecondary education is a unique opportunity for students to learn and have their ideas and beliefs challenged. However, universities receiving hundreds of millions of federal funds annually have denied
students that opportunity and have been hijacked to become venues for the promotion of terrorism, antisemitic harassment and intimidation, unlawful encampments, and in some cases, assaults and riots.
The House of Representatives will not countenance the use of federal funds to indoctrinate students into hateful, antisemitic, anti-American supporters of terrorism. Investigations into campus antisemitism by the Committee on Education and the Workforce and the Committee on Ways and Means have been expanded into a Congress-wide probe across all relevant jurisdictions to address this national crisis. The undersigned Committees will conduct oversight into the use of federal funds at MIT and its learning environment under authorities granted to each Committee.
• The Committee on Education and the Workforce has been investigating your institution since December 7, 2023. The Committee has broad jurisdiction over postsecondary education, including its compliance with Title VI of the Civil Rights Act, campus safety concerns over disruptions to the learning environment, and the awarding of federal student aid under the Higher Education Act.
• The Committee on Oversight and Accountability is investigating the sources of funding and other support flowing to groups espousing pro-Hamas propaganda and engaged in antisemitic harassment and intimidation of students. The Committee on Oversight and Accountability is the principal oversight committee of the US House of Representatives and has broad authority to investigate “any matter” at “any time” under House Rule X.
• The Committee on Ways and Means has been investigating several universities since November 15, 2023, when the Committee held a hearing entitled From Ivory Towers to Dark Corners: Investigating the Nexus Between Antisemitism, Tax-Exempt Universities, and Terror Financing. The Committee followed the hearing with letters to those institutions on January 10, 202
Biological screening of herbal drugs: Introduction and Need for
Phyto-Pharmacological Screening, New Strategies for evaluating
Natural Products, In vitro evaluation techniques for Antioxidants, Antimicrobial and Anticancer drugs. In vivo evaluation techniques
for Anti-inflammatory, Antiulcer, Anticancer, Wound healing, Antidiabetic, Hepatoprotective, Cardio protective, Diuretics and
Antifertility, Toxicity studies as per OECD guidelines
Unit 8 - Information and Communication Technology (Paper I).pdfThiyagu K
This slides describes the basic concepts of ICT, basics of Email, Emerging Technology and Digital Initiatives in Education. This presentations aligns with the UGC Paper I syllabus.
Macroeconomics- Movie Location
This will be used as part of your Personal Professional Portfolio once graded.
Objective:
Prepare a presentation or a paper using research, basic comparative analysis, data organization and application of economic information. You will make an informed assessment of an economic climate outside of the United States to accomplish an entertainment industry objective.
The French Revolution, which began in 1789, was a period of radical social and political upheaval in France. It marked the decline of absolute monarchies, the rise of secular and democratic republics, and the eventual rise of Napoleon Bonaparte. This revolutionary period is crucial in understanding the transition from feudalism to modernity in Europe.
For more information, visit-www.vavaclasses.com
The Roman Empire A Historical Colossus.pdfkaushalkr1407
The Roman Empire, a vast and enduring power, stands as one of history's most remarkable civilizations, leaving an indelible imprint on the world. It emerged from the Roman Republic, transitioning into an imperial powerhouse under the leadership of Augustus Caesar in 27 BCE. This transformation marked the beginning of an era defined by unprecedented territorial expansion, architectural marvels, and profound cultural influence.
The empire's roots lie in the city of Rome, founded, according to legend, by Romulus in 753 BCE. Over centuries, Rome evolved from a small settlement to a formidable republic, characterized by a complex political system with elected officials and checks on power. However, internal strife, class conflicts, and military ambitions paved the way for the end of the Republic. Julius Caesar’s dictatorship and subsequent assassination in 44 BCE created a power vacuum, leading to a civil war. Octavian, later Augustus, emerged victorious, heralding the Roman Empire’s birth.
Under Augustus, the empire experienced the Pax Romana, a 200-year period of relative peace and stability. Augustus reformed the military, established efficient administrative systems, and initiated grand construction projects. The empire's borders expanded, encompassing territories from Britain to Egypt and from Spain to the Euphrates. Roman legions, renowned for their discipline and engineering prowess, secured and maintained these vast territories, building roads, fortifications, and cities that facilitated control and integration.
The Roman Empire’s society was hierarchical, with a rigid class system. At the top were the patricians, wealthy elites who held significant political power. Below them were the plebeians, free citizens with limited political influence, and the vast numbers of slaves who formed the backbone of the economy. The family unit was central, governed by the paterfamilias, the male head who held absolute authority.
Culturally, the Romans were eclectic, absorbing and adapting elements from the civilizations they encountered, particularly the Greeks. Roman art, literature, and philosophy reflected this synthesis, creating a rich cultural tapestry. Latin, the Roman language, became the lingua franca of the Western world, influencing numerous modern languages.
Roman architecture and engineering achievements were monumental. They perfected the arch, vault, and dome, constructing enduring structures like the Colosseum, Pantheon, and aqueducts. These engineering marvels not only showcased Roman ingenuity but also served practical purposes, from public entertainment to water supply.
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Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
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It is possible to hide or invisible some fields in odoo. Commonly using “invisible” attribute in the field definition to invisible the fields. This slide will show how to make a field invisible in odoo 17.
1. Page 1 of 13
Breakdown of Amino Acids
Amino acids are degraded to compounds that can be metabolized to CO2 and H2O or used in
gluconeogenesis. Indeed, oxidative breakdown of amino acids typically accounts for 10 to
15% of the metabolic energy generated by animals. “Standard” amino acids are degraded to
one of seven metabolic intermediates: pyruvate, α-ketoglutarate, succinyl-CoA, fumarate,
oxaloacetate, acetyl-CoA, or acetoacetate (Fig. 1). The amino acids can therefore be divided
into two groups based on their catabolic pathways:
1. Glucogenic amino acids, which are degraded to pyruvate, α-ketoglutarate, succinyl-CoA,
fumarate, or oxaloacetate and are therefore glucose precursors.
2. Ketogenic amino acids, which are broken down to acetyl-CoA or acetoacetate and can
thus be converted to fatty acids or ketone bodies.
Some amino acids are precursors of both carbohydrates and ketone bodies. Since animals
lack any metabolic pathways for the net conversion of acetyl-CoA or acetoacetate to
gluconeogenic precursors, no net synthesis of carbohydrates is possible from the purely
ketogenic amino acids Lys and Leu. In studying the specific pathways of amino acid
breakdown, we shall organize the amino acids into groups that are degraded to each of the
seven metabolites mentioned above.
2. Page 2 of 13
Alanine, Cysteine, Glycine, Serine, and Threonine Are Degraded to Pyruvate
Five amino acids—alanine, cysteine, glycine, serine, and threonine—are broken down to
yield pyruvate (Fig. 2).
Alanine is straightforwardly transaminated to pyruvate. Serine is converted to pyruvate
through dehydration by serine dehydratase. This PLP-dependent enzyme, like the
aminotransferases, forms a PLP–amino acid Schiff base which facilitates the removal of the
amino acid’s α-hydrogen atom. In the serine dehydratase reaction, however, the Cα
carbanion breaks down with the elimination of the amino acid’s Cβ OH, rather than with
tautomerization, so that the substrate undergoes α,β elimination of H2O rather than
deamination (Fig. 3).The product of the dehydration, the enamine aminoacrylate,
tautomerizes nonenzymatically to the corresponding imine, which spontaneously
hydrolyzes to pyruvate and ammonia.
3. Page 3 of 13
Glycine is converted to pyruvate by first being converted to serine by the enzyme serine
hydroxymethyltransferase, another PLP-containing enzyme (Fig. 2, Reaction 4). This
enzyme uses N5,N10-methylenetetrahydrofolate (N5,N10-methylene-THF) as a one-
carbon donor. The methylene group of the THF cofactor is obtained from a second glycine
in Reaction 3 of Fig. 2, which is catalyzed by the glycine cleavage system (called the
glycine decarboxylase multienzyme system in plants). This enzyme is a multiprotein
complex that resembles pyruvate dehydrogenase.
5. Page 5 of 13
The serine dehydratase reaction entails a PLP-catalyzed elimination of water across the
bond between the and carbons (step 1 ), leading eventually to the production of pyruvate
(steps 2 through 4 ). In the serine hydroxymethyltransferase reaction, a PLP-stabilized
carbanion on the carbon of glycine (product of step 1 ) is a key intermediate in the transfer
of the methylene group (as -CH2-OH) from N5,N10-methylenetetrahydrofolate to form
serine. This reaction is reversible. The glycine cleavage enzyme is a multienzyme
complex, with components P, H, T, and L. The overall reaction, which is reversible,
converts glycine to CO2 and NH4+ , with the second glycine carbon taken up by
tetrahydrofolate to form N5,N10-methylenetetrahydrofolate
The glycine cleavage system mediates the major route of glycine degradation in
mammalian tissues. An inherited deficiency of the glycine cleavage system causes the
disease nonketotic hyperglycinemia, which is characterized by mental retardation and
accumulation of large amounts of glycine in body fluids.
Threonine is both glucogenic and ketogenic since it generates both pyruvate and acetyl-
CoA. Its major route of breakdown is through threonine dehydrogenase (Fig. 2, Reaction
6), producing α-amino-β-ketobutyrate, which is converted to acetyl-CoA and glycine by α-
amino-β-ketobutyrate lyase (Fig. 2, Reaction 7). The glycine can be converted, through
serine, to pyruvate.
Serine Hydroxymethyltransferase Catalyzes PLP-Dependent Cα ___ Cβ Bond
Formation and Cleavage. Threonine can also be converted directly to glycine and
acetaldehyde (which is subsequently oxidized to acetyl-CoA) via Reaction 5 of Fig. 2, which
breaks threonine’s Cα ___ Cβ bond. This PLP-dependent reaction is catalyzed by serine
hydroxymethyl-transferase, the same enzyme that adds a hydroxymethyl group to glycine
6. Page 6 of 13
to produce serine (Fig. 2, Reaction 4). In the glycine serine reaction, the amino acid’s
Cα___H bond is cleaved (as occurs in transamination) and a Cα ___Cβ bond is formed. In
contrast, the degradation of threonine to glycine by serine hydroxymethyltransferase acts
in reverse, beginning with Cα— Cβ bond cleavage:
With the cleavage of any of the bonds to Cα, the PLP group delocalizes the electrons of the
resulting carbanion. This feature of PLP action is the key to understanding how the same
amino acid–PLP Schiff base can undergo cleavage of different bonds to Cα in different
enzymes.
7. Page 7 of 13
Cysteine can be converted to pyruvate via several routes in which the sulfhydryl group is
released as H2S, SO32- , or SCN-.
HC
+
NH3
CH2
COO-
SH
HC
+
NH3
CH2
COO-
SO2
-
H2C
+
NH3
CH2
SO2
-
Cysteine Cysteinesulfinate
Hypotaurine
H2C
+
NH3
CH2
SO3
-
Taurine
Pyruvate
KG
Glu
HSO3
-Bisulfite
HSO3
-
+ O2 + H2O SO4
2-
+ H2O2 + H+
Sulfite
oxidase
HC
+
NH3
CH2
COO-
SH
HC +
NH3
CH2
COO-
S
Cysteine
Cysteine
H2O
NH4
+
SH
+ PyruvateThiocysteine
HC
+
NH3
CH2
COO-
SH
KG
Glu
C O
CH2
COO-
SH
B-Mercaptopyruvate
SSO3
2-
SO3
2- Pyruvate
3-mercaptopyruvate
sulfurtransferase
Thiosulfate
Thiocysteine + Thiosulfate + CN-
Rhodanese
Cysteine + Thiocyanate
8. Page 8 of 13
Asparagine and Aspartate Are Degraded to Oxaloacetate
Transamination of aspartate leads directly to oxaloacetate:
Asparagine is also converted to oxaloacetate in this manner after its hydrolysis to aspartate by
L-asparaginase:
Interestingly, L-asparaginase is an effective chemotherapeutic agent in the treatment of cancers
that must obtain asparagine from the blood, particularly acute lymphoblastic leukemia.
Arginine, Glutamate, Glutamine, Histidine, and Proline Are Degraded to α-Ketoglutarate
Arginine, glutamine, histidine, and proline are all degraded by conversion to glutamate , which in
turn is oxidized to α-ketoglutarate by glutamate dehydrogenase. Conversion of glutamine to
glutamate involves only one reaction: hydrolysis by glutaminase. In the kidney, the action of
glutaminase produces ammonia, which combines with a proton to form the ammonium ion
(NH4
+
) and is excreted. During metabolic acidosis, kidney glutaminase helps eliminate excess
acid. Although free NH3 in the blood could serve the same acid-absorbing purpose, ammonia is
toxic. It is therefore converted to glutamine by glutamine synthetase in the liver. Glutamine
therefore acts as an ammonia transport system between the liver, where much of it is
synthesized, and the kidneys, where it is hydrolyzed by glutaminase.
9. Page 9 of 13
Histidine’s conversion to glutamate is more complicated: It is nonoxidatively deaminated, then it
is hydrated, and its imidazole ring is cleaved to form N-formiminoglutamate. The formimino
group is then transferred to tetrahydrofolate, forming glutamate and N5
-formimino-
tetrahydrofolate. Both arginine and proline are converted to glutamate through the intermediate
formation of glutamate-5-semialdehyde.
Isoleucine, Methionine, and Valine Are Degraded to Succinyl-CoA
Isoleucine, methionine, and valine have complex degradative pathways that all yield propionyl-
CoA, which is also a product of odd-chain fatty acid degradation. Propionyl-CoA is converted to
succinyl-CoA by a series of reactions requiring biotin and coenzyme B12).
Methionine Breakdown Involves Synthesis of S-Adenosylmethionine and Cysteine.
Methionine degradation (Fig.) begins with its reaction with ATP to form S-adenosylmethionine
(SAM; alternatively AdoMet). This sulfonium ion’s highly reactive methyl group makes it an
important biological methylating agent. For instance, SAM is the methyl donor in the synthesis
of phosphatidylcholine from phosphatidylethanolamine. Donation of a methyl group from SAM
leaves S-adenosylhomocysteine, which is then hydrolyzed to adenosine and homocysteine. The
homocysteine can be methylated to re-form methionine via a reaction in which
N5-methyltetrahydrofolate is the methyl donor. Alternatively, the homocysteine can combine
with serine to yield cystathionine, which subsequently forms cysteine (cysteine biosynthesis) and
10. Page 10 of 13
α-ketobutyrate. The α-ketobutyrate continues along the degradative pathway to propionyl-CoA
and then succinyl-CoA. High homocysteine levels are associated with disease.
Homocysteine, a Marker of Disease
The cellular level of homocysteine depends on its rate of synthesis through methylation reactions
utilizing SAM (Fig., Reactions 2 and 3) and its rate of utilization through remethylation to form
methionine (Fig., Reaction 4) and reaction with serine to form cystathionine in the cysteine
biosynthetic pathway (Fig., Reaction 5). An increase in homocysteine levels leads to
hyperhomocysteinemia, elevated concentrations of homocysteine in the blood, which is
associated with cardiovascular disease. The link was first discovered in individuals with
homocysteinuria, a disorder in which excess homocysteine is excreted in the urine. These
individuals develop atherosclerosis as children, possibly because homocysteine causes oxidative
damage to the walls of blood vessels even in the absence of elevated LDL levels.
Hyperhomocysteinemia is also associated with neural tube defects, the cause of a variety of
severe birth defects including spina bifida (defects in the spinal column that often result in
paralysis) and anencephaly (the invariably fatal failure of the brain to develop, which is the
leading cause of infant death due to congenital anomalies).
Hyperhomocysteinemia is readily controlled by ingesting the vitamin precursors of the
coenzymes that participate in homocysteine breakdown, namely, B6 (pyridoxine, the PLP
precursor), B12 , and folate. Folate, especially, alleviates hyperhomocysteinemia; its
11. Page 11 of 13
administration to pregnant women dramatically reduces the incidence of neural tube defects in
newborns. Because neural tube development is one of the earliest steps of embryogenesis,
women of childbearing age are encouraged to consume adequate amounts of folate even before
they become pregnant.
Around 10% of the population is homozygous for an Ala → Val mutation in N5
,N10
-methylene-
tetrahydrofolate reductase (MTHFR), which catalyzes the conversion of N5
,N10
-methylene-
THF to N5
-methyl-THF. This reaction generates the N5
-methyl-THF required to convert
homocysteine to methionine (Fig. 21-18. The mutation does not affect the enzyme’s reaction
kinetics but instead increases the rate at which its essential flavin cofactor dissociates. Folate
derivatives that bind to the enzyme decrease the rate of flavin loss, thus increasing the enzyme’s
overall activity and decreasing the homocysteine concentration. The prevalence of the MTHFR
mutation in the human population suggests that it has (or once had) some selective advantage;
however, this is as yet a matter of speculation.
Tetrahydrofolates Are One-Carbon Carriers.
Many biosynthetic processes involve the addition of a C1 unit to a metabolic precursor. In
most carboxylation reactions (e.g., pyruvate carboxylase), the enzyme uses a biotin
cofactor. In some reactions, S-adenosylmethionine functions as a methylating agent.
However, tetrahydrofolate (THF) is more versatile than either of those cofactors because it
can transfer C1 units in several oxidation states. THF is a 6-methylpterin derivative linked
in sequence to a p-aminobenzoic acid and a Glu residue:
Up to five additional Glu residues are linked to the first glutamate via isopeptide bonds to
form a polyglutamyl tail. THF is derived from the vitamin folic acid (Latin: folium, leaf), a
doubly oxidized form of THF that must be enzymatically reduced before it becomes an
active coenzyme. Both reductions are catalyzed by dihydrofolate reductase (DHFR).
12. Page 12 of 13
Mammals cannot synthesize folic acid, so it must be provided in the diet or by intestinal
microorganisms. C1 units are covalently attached to THF at positions N5, N10, or both N5
and N10. These C1 units, which may be at the oxidation levels of formate, formaldehyde, or
methanol (Table), are all interconvertible by enzymatic redox reactions.
THF acquires C1 units in the conversion of serine to glycine by serine hydroxymethyl-
transferase, in the cleavage of glycine, and in histidine breakdown. The C1 units carried by
THF are used in the synthesis of thymine nucleotides and in the synthesis of methionine
from homocysteine. By promoting the latter process, supplemental folate helps prevent
diseases associated with abnormally high levels of homocysteine.
13. Page 13 of 13
Sulfonamides (sulfa drugs) such as sulfanilamide are antibiotics that are structural
analogs of the p-aminobenzoic acid constituent of THF:
They competitively inhibit bacterial synthesis of THF at the paminobenzoic acid
incorporation step, thereby blocking THF-requiring reactions.The inability of mammals to
synthesize folic acid leaves them unaffected by sulfonamides, which accounts for the
medical utility of these widely used antibacterial agents.