Download MBBS Biochemistry PPT 79 One Carbon Metabolism And Its Clinical Significance Lecture Notes

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Specific Learning Objectives

Describe roles of folic acid, cobalamin and S-adenosylmethionine (SAM)

in transfer of one carbon units between molecules, and apply their

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relevance to disease states

Describe synthesis of S-adenosylmethionine and its role in methylation

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reactions

Explain how a cobalamin deficiency leads to a secondary folate deficiency
Introduction

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Human body cannot synthesize folic acid

Its also called vitamin B9 give rise to tetrahydrofolate (THF), carry one

carbon groups ex. Methyl group

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Intestines releases mostly N5-methy-THF into blood

One-carbon (1C) metabolism, mediated by folate cofactor, supports

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biosynthesis of purines and pyrimidines, aa homeostasis (glycine, serine

and methionine)

Table 14.4: DM Vasudevan' s Textbook of Biochemistry for Medical Students 6th edition

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Enzyme co-factors involved in aa catabolism

Involves one of three co-factors: Biotin, Tetrahydrofolate (THF) and S-

adenosylmethionine (SAM)

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These cofactors transfer one-carbon groups in different oxidation states:

1. Biotin transfers carbon in its most oxidized state CO2, it require for

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catabolism and utilization of branched chain aa

? Biotin responsible for carbon dioxide transfer in several carboxylase

enzymes

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Cont--

2. Tetrahydrofolate (THF) transfers one-carbon groups in intermediate

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oxidation states and as methyl groups
? Tetrahydrobiopterin (BH4, THB) is a cofactor of degradation of

phenylalanine

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? Oxidised form of THF, folate is vitamin for mammals
? It converted into THF by DHF reductase

3. S-adenosylmethionine (SAM) transfers methyl groups, most reduced state

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of carbon

THF and SAM imp in aa and nucleotide metabolism
SAM

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used in biosynthesis of creatine, phosphatidylcholine,

plasmenylcholine and epinephrine, also methylated DNA, RNA and proteins
Enzymes use cobalamin as a cofactor

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1. Methionine synthase: transfer methyl group from 5-methyl-THF to

homocysteine in activated methyl group, requires cofactor methyl

cobalamin

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? Rate of cobalamin dependent methyl transfer to homocysteine is

abnormally low in patients with cobalamin deficiency

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2. Methylmalonyl-CoA Mutase: require 5-deoxyadenosyl cobalamin and

catalyze reaction in conversion of Propionyl-CoA arises from methionine

metabolism,

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Loading THF with one carbon groups

Serine, glycine, histidine and formate are directly contribute to one

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carbon metabolism

In irreversible reaction, 5,10-methylene-THF into 5-methyl-THF, by

MTHFR (methyl tetrahydrofolate reductase), imp in understanding

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induction of 2? folate deficiency by a cobalamin deficiency
Overview of reactions that donate one-carbon

groups to tetrahydrofolic acid

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Fig 36.3. Netter's Essential Biochemistry, 1st Ed

Overview of the use of one-carbon groups from folates

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Fig 36.4. Netter's Essential Biochemistry, 1st Ed
Effects of folate deficiency on one-carbon metabolism

Fig 36.11. Netter's Essential Biochemistry, 1st Ed

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Synthesis of methionine and S-adenosylmethionine in an activated-methyl cycle

Fig 36.6. Netter's Essential Biochemistry, 1st Ed
Conversion of one carbon units on THF

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1? source of one-carbon units for THF is carbon removed in conversion of

serine to glycine, produce 5,10 methyleneTHF

SAM synthesized from ATP and methionine by methionine adenosyl

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transferase

Transfer of methyl group from SAM to S-adenosyl-homocysteine, broken

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down to homocysteine and adenosine

Cont--

Methionine regenerated by transfer of methyl group to homocysteine in

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reaction catalyzed by methionine synthase

Methionine synthase activity depends on two vit: N5-methy-THF and

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cobalamin

In fasting state, homocysteine stays in activated methyl group cycle.

Methionine reconverted to SAM to complete activated methyl cycle

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Folate mediated one carbon metabolism

Donate carbon atom for DNA

5,10-Methylene THF

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synthesis

Intermediate Oxidation state

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Methylene THF reductase

Methionine synthase

Most reduced oxidation state

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5,10-Methenyl THF

Most oxidized state

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10-Formyl-THF

Most oxidized state

5-Formyl THF

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Most oxidized state

Gregory S. Ducker and Joshua D Rabinowitz 2017

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Folate Trap

Conversion of 5,10-methylene-THF into 5-methyl-THF, by MTHFR

(methyl tetrahydrofolate reductase), is irreversible

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Use of 5-methyl-THF and to maintain folate cycle consists in vit-B12-

dependent remethylation of homocysteine to methionine (regenerating

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THF)

Methyl group transfer is dependent on 5-methyl-THF and availability of

vit-B12

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Cont--

In vit B12 deficiency, in spite of sufficient availability of folates (and 5-

methyl-THF), deficiency of active THF arises, this situation is called a

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`folate trap'

Because concentration of 5-methyl-THF continues to rise due to it being

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prevented from releasing methyl groups, a `metabolic dead-end situation'

develops, which leads to blockage of methylation cycle.

Cont--

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Co-factors for C1-transfers decrease and replication as well as cell

division rate are reduced

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Hence, decreasing activity of methionine synthase under vitamin-B12

deficiency with secondary disorders affecting folate metabolism and

insufficient de-novo synthesis of purines and pyrimidines

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Deficiency in active folic acids first affects quickly dividing and highly

proliferating haematopoiesis cells in bone marrow and lead to

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pancytopenia
Folic acid deficiency

It may result from limited diets, when food is cooked at high

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temperatures for long periods, which destroys vitamin

Intestinal diseases (celiac disease), are characterized by folic acid

deficiency caused by malabsorption

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Inability to absorb folate is rare.

Folate deficiency is usually in newborns and produces symptoms of

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megaloblastic anemia

Cont--

Besides anemia, mental and other CNS symptoms are in patients

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with folate deficiency, and all respond to continuous therapy although

permanent damage appears to be caused by delayed or inadequate

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treatment
Megaloblastic anemia

1. Folate deficiency:
Vit B12 and folate linked in metabolic pathways

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Vit B12 deficiency leads to pernicious anemia, seen in individuals

having defect in intestinal absorption pathways due to lack of intrinsic

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factor for this vitamin

It causes symptoms like anaemia and neurological disorders

Cont--

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Conversion of 5,10-methylene-THF into 5-methyl-THF, by MTHFR

(methyl tetrahydrofolate reductase), is irreversible

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If coenzyme B not available for synthesis of methyl-cobalamin, then

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metabolic folates becomes trapped in 5-methyl form.

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This anemia associated with Vit B deficiency called megaloblastic

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anemia

Treat pernicious anemia by Vit B12 and folate
Clinical-cases discussed

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Thank you