Download MBBS Biochemistry PPT 34 Biochemistry I Lecture Notes

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Department of Biochemistry

Learning Objectives

? One Carbon Metabolism

? Catabolism of the Carbon Skeletons of amino acids and

related disorders:

. Alanine, glycine, serine, cysteine, tryptophan, and threonine degraded to

pyruvate

. Tryptophan, lysine, phenylalanine, tyrosine, leucine, isoleucine, and

threonine degraded to Acetyl-CoA
Enzyme co-factors involved in aa catabolism

Involves one of the three co-factors: Biotin, Tetrahydrofolate

(THF) and S-adenosylmethione (SAM)

? These cofactors transfer one-carbon groups in different

oxidation states

? Biotin transfers carbon in its most oxidized state CO it require

2,

for catabolism and utilization of branched chain aa

Cont--

? Tetrahydrofolate transfers one-carbon groups in intermediate

oxidation states and as methyl groups

? S-adenosylmethionine transfers methyl groups, the most

reduced state of carbon

Tetrahydrobiopterin (BH , THB) is a cofactor of the degradation of

4

phenylalanine
One-Carbon Metabolism

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

supports biosynthesis of purines and pyrimidines, aa

homeostasis (glycine, serine and methionine)

? Folate (Vit B9), precursor for formation of THF by dihydrofolate

reductase

? THF is active form that carries 1-carbon groups such as formyl,

methenyl, methylene and methyl, act as cofactor, imp for

nucleic acid and amino acid synthesis

Table 14.4: DM Vasudevan' s Textbook of Biochemistry for Medical Students 6th edition
Folate mediated one carbon metabolism

Donate carbon atom for DNA

5,10-Methylene THF

synthesis

Intermediate Oxidation state

Methylene THF reductase

Methionine synthase

Most reduced oxidation state

5,10-Methenyl THF

Most oxidized state

10-Formyl-THF

Most oxidized state

5-Formyl THF

Most oxidized state

Gregory S. Ducker and Joshua D Rabinowitz 2017

Folate trap

? Conversion of 5,10-methylen-THF into 5-methyl-THF, by

MTHFR (methyl tetrahydrofolate reductase), is irreversible

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

B12-dependent remethylation of homocysteine to methionine

(regenerating THF)

? Methyl group transfer is dependent on 5-methyl-THF and

availability of vit-B12
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 `folate trap'

? Because concentration of 5-methyl-THF continues to rise due to

it being prevented from releasing methyl groups, a `metabolic

dead-end situation' develops, which leads to blockage of

methylation cycle.

Cont--

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

cell division rate are reduced

? 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

? Deficiency in active folic acids first affects quickly dividing and

highly proliferating haematopoiesis cells in bone marrow and

lead to pancytopenia
Folic acid deficiency

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

temperatures for long periods, which destroys the vitamin

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

acid deficiency caused by malabsorption

? Inability to absorb folate is rare. Folate deficiency is usually in

newborns and produces symptoms of megaloblastic anemia

Cont--

? Besides the anemia, mental and other CNS symptoms are in

patients with folate deficiency, and all respond to continuous

therapy although permanent damage appears to be caused by

delayed or inadequate treatment
Catabolism of the Carbon Skeletons of aa

and related disorders

Introduction

Carbon skeletons are generally conserved as:
? Carbohydrate, via gluconeogenesis,
? Fatty acid via fatty acid synthesis pathways.

These pathways converge to form seven intermediate products:
? oxaloacetate, -ketoglutarate, pyruvate, fumarate, succinyl

coenzyme A (CoA) , acetyl CoA, and acetoacetate
Cont--

These products directly enter the pathways of intermediary

metabolism:
? Resulting either in the synthesis of glucose or lipid or in the

production of energy through their oxidation to CO and water

2

by the citric acid cycle

Catabolic pathways of six aa to Pyruvate

Fig18.19: Lehninger Principles of Biochemistry by David L Nelson
Cont--
Glycine cleavage system is multienzyme complex: It consists of four

proteins:

1. PLP-dependent glycine decarboxylase (P-protein)

2. Lipoamide-containing aminomethyl carrier (H-protein), which carries

aminomethyl group remaining after glycine decarboxylation

3. N5,N10-methylene-THF synthesizing enzyme aminomethyltransferase (AMT)

(T-protein), which accepts a methylene group from aminomethyl carrier, amino

group is released as ammonia

4. NAD+-dependent, FAD-requiring dihydrolipoyl dehydrogenase (L-protein), a

protein shared by and known as E3 in pyruvate dehydrogenase complex

Disorder related to glycine

Non-ketotic hyperglycinemia (NKH)

? Humans with serious defects in glycine cleavage system activity

due to absence of one of the components of glycine cleavage

system

? The condition is characterized by elevated serum levels of

glycine, leading to mental retardation and death in very early

childhood
Cont--

? In one of the glycine degradation pathway, glycine is converted

into glyoxylate by D-amino acid oxidase

? Glycine is the precursor of glyoxalate, which can be

transaminated back to glycine or oxidized to oxalate by lactate

dehydrogenase

? Excessive production of oxalate forms the insoluble calcium

oxalate salt, lead to kidney stones.

Two pathways catabolize cysteine

Fig 29.9: Harper's Illustrated Biochemistry 30th Edition
Disorders related to Cysteine

? Cystinuria is caused by mutations in SLC3A1 and SLC7A9 genes.

? These defects prevent reabsorption of basic positively charged aa

(Cysteine, lysine, ornithine and arginine)

? Under normal condition, these proteins allow certain aa including

cysteine to be reabsorbed into blood from filtered fluid that will

become urine

? Mutations in either of these genes disrupt the ability of this

transporter protein exist in kidney tubules to reabsorb these aa,

allowing them to excretion of these aa in urin

Catabolic pathway of Hydroxyproline

Harper's Illustrated Biochemistry 30th Edition
Disorders related to Hydroxyporoline

? A defect in 4-hydroxyproline dehydrogenase results in

hyperhydroxyprolinemia, an excess of free hydroxyproline in the

plasma and urine, it may be associated with mental retardation

? A defect in glutamate--semialdehyde dehydrogenase/ 1-pyrroline-3-

hydroxyl-5-carboxylate dehydrogenase results in type II

hyperprolinemia which is accompanied by excretion of 1-pyrroline-

3-hydroxy-5-carboxylate

? Type II hyperprolinemia is a rare form of disorder may appear benign

at time but often involves seizures, convulsions and intellectual

disability.

Catabolism of Tryptophan to -Ketoadipate

Fig 29.16. Harper's Illustrated Biochemistry 30th Edition
Disorder related to Tryptophan

Hartnup disease: In catabolism of Typ, kynureninase requires

PLP (active form of vit B6), acts on 3-L hydroxylkynurenine

? Defect in kynureninase limits tryptophan availability for niacin

biosynthesis, cause reduced synthesis of NAD+ and NADP+

leads to pellagra-like signs and symptoms.

? Due to lack of PLP, Kynureninase reaction blocked and 3-L

hydroxylkynurenine is diverted and form xanthurenate catalyzed

by Kynurenine transferases

Cont--

? Elevated levels of xanthurenate shows vit B6 deficiency

? Hartnup disease reflects impaired intestinal and renal transport

of tryptophan and other neutral aa

? Indole derivatives of unabsorbed tryptophan formed by

intestinal bacteria are excreted
Catabolic pathways of seven aa to Acetyl-CoA

Threonine yield some acetyl CoA also

Fig18.21: Lehninger Principles of Biochemistry by David L Nelson

Disorder related to Lysine

? Genetic defect in saccharopine dehydrogenase that catalyzes

lysine into saccharopine results in hyperlysinemia and

hyperlysinuria (elevated levels of lysine in the blood and urine,

respectively) along with mental and physical retardation.
Group Discussion

? Subtopics of previous class discussed in groups.

Thank you

This post was last modified on 05 April 2022