Download MBBS (Bachelor of Medicine, Bachelor of Surgery) 1st year (First Year) Biochemistry ppt lectures Topic 34 Biochemistry I Notes. - biochemistry notes pdf, biochemistry mbbs 1st year notes pdf, biochemistry mbbs notes pdf, biochemistry lecture notes, paramedical biochemistry notes, medical biochemistry pdf, biochemistry lecture notes 2022 ppt, biochemistry pdf.
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