? Catabolism of the Carbon Skeletons of amino acids and
related disorders:
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. Alanine, glycine, serine, cysteine, tryptophan, and threonine degraded to
pyruvate
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. Tryptophan, lysine, phenylalanine, tyrosine, leucine, isoleucine, andthreonine degraded to Acetyl-CoA
Enzyme co-factors involved in aa catabolism
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Involves one of the three co-factors: Biotin, Tetrahydrofolate(THF) and S-adenosylmethione (SAM)
? These cofactors transfer one-carbon groups in different
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oxidation states
? Biotin transfers carbon in its most oxidized state CO it require
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2,for catabolism and utilization of branched chain aa
Cont--
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? Tetrahydrofolate transfers one-carbon groups in intermediate
oxidation states and as methyl groups
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? S-adenosylmethionine transfers methyl groups, the mostreduced state of carbon
Tetrahydrobiopterin (BH , THB) is a cofactor of the degradation of
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4
phenylalanine
One-Carbon Metabolism
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? One-carbon (1C) metabolism, mediated by the folate cofactor,
supports biosynthesis of purines and pyrimidines, aa
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homeostasis (glycine, serine and methionine)? Folate (Vit B9), precursor for formation of THF by dihydrofolate
reductase
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? THF is active form that carries 1-carbon groups such as formyl,
methenyl, methylene and methyl, act as cofactor, imp for
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nucleic acid and amino acid synthesisTable 14.4: DM Vasudevan' s Textbook of Biochemistry for Medical Students 6th edition
Folate mediated one carbon metabolism
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Donate carbon atom for DNA5,10-Methylene THF
synthesis
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Intermediate Oxidation state
Methylene THF reductase
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Methionine synthaseMost reduced oxidation state
5,10-Methenyl THF
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Most oxidized state
10-Formyl-THF
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Most oxidized state5-Formyl THF
Most oxidized state
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Gregory S. Ducker and Joshua D Rabinowitz 2017
Folate trap
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? Conversion of 5,10-methylen-THF into 5-methyl-THF, byMTHFR (methyl tetrahydrofolate reductase), is irreversible
? Use of 5-methyl-THF and to maintain folate cycle consists in vit-
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B12-dependent remethylation of homocysteine to methionine
(regenerating THF)
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? Methyl group transfer is dependent on 5-methyl-THF andavailability of vit-B12
Cont--
? In vit B12 deficiency, in spite of sufficient availability of folates
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(and 5-methyl-THF), deficiency of active THF arises, this
situation is called a `folate trap'
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? Because concentration of 5-methyl-THF continues to rise due toit being prevented from releasing methyl groups, a `metabolic
dead-end situation' develops, which leads to blockage of
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methylation cycle.
Cont--
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? Co-factors for C1-transfers decrease and replication as well ascell division rate are reduced
? Hence, decreasing activity of methionine synthase under
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vitamin-B12 deficiency with secondary disorders affecting folate
metabolism and insufficient de-novo synthesis of purines and
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pyrimidines? Deficiency in active folic acids first affects quickly dividing and
highly proliferating haematopoiesis cells in bone marrow and
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lead to 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 the vitamin
? Intestinal diseases (celiac disease), are characterized by folic
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acid deficiency caused by malabsorption? Inability to absorb folate is rare. Folate deficiency is usually in
newborns and produces symptoms of megaloblastic anemia
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Cont--
? Besides the anemia, mental and other CNS symptoms are in
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patients with folate deficiency, and all respond to continuoustherapy although permanent damage appears to be caused by
delayed or inadequate treatment
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Catabolism of the Carbon Skeletons of aaand related disorders
Introduction
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Carbon skeletons are generally conserved as:
? Carbohydrate, via gluconeogenesis,
? Fatty acid via fatty acid synthesis pathways.
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These pathways converge to form seven intermediate products:? oxaloacetate, -ketoglutarate, pyruvate, fumarate, succinyl
coenzyme A (CoA) , acetyl CoA, and acetoacetate
Cont--
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These products directly enter the pathways of intermediary
metabolism:
? Resulting either in the synthesis of glucose or lipid or in the
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production of energy through their oxidation to CO and water
2
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by the citric acid cycleCatabolic pathways of six aa to Pyruvate
Fig18.19: Lehninger Principles of Biochemistry by David L Nelson
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Cont--Glycine cleavage system is multienzyme complex: It consists of four
proteins:
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1. PLP-dependent glycine decarboxylase (P-protein)2. Lipoamide-containing aminomethyl carrier (H-protein), which carries
aminomethyl group remaining after glycine decarboxylation
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3. N5,N10-methylene-THF synthesizing enzyme aminomethyltransferase (AMT)
(T-protein), which accepts a methylene group from aminomethyl carrier, amino
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group is released as ammonia4. NAD+-dependent, FAD-requiring dihydrolipoyl dehydrogenase (L-protein), a
protein shared by and known as E3 in pyruvate dehydrogenase complex
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Disorder related to glycine
Non-ketotic hyperglycinemia (NKH)
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? Humans with serious defects in glycine cleavage system activitydue to absence of one of the components of glycine cleavage
system
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? The condition is characterized by elevated serum levels of
glycine, leading to mental retardation and death in very early
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childhoodCont--
? In one of the glycine degradation pathway, glycine is converted
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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
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dehydrogenase
? Excessive production of oxalate forms the insoluble calcium
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oxalate salt, lead to kidney stones.Two pathways catabolize cysteine
Fig 29.9: Harper's Illustrated Biochemistry 30th Edition
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Disorders related to Cysteine? Cystinuria is caused by mutations in SLC3A1 and SLC7A9 genes.
? These defects prevent reabsorption of basic positively charged aa
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(Cysteine, lysine, ornithine and arginine)
? Under normal condition, these proteins allow certain aa including
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cysteine to be reabsorbed into blood from filtered fluid that willbecome urine
? Mutations in either of these genes disrupt the ability of this
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transporter protein exist in kidney tubules to reabsorb these aa,
allowing them to excretion of these aa in urin
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Catabolic pathway of HydroxyprolineHarper's Illustrated Biochemistry 30th Edition
Disorders related to Hydroxyporoline
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? A defect in 4-hydroxyproline dehydrogenase results inhyperhydroxyprolinemia, an excess of free hydroxyproline in the
plasma and urine, it may be associated with mental retardation
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? A defect in glutamate--semialdehyde dehydrogenase/ 1-pyrroline-3-
hydroxyl-5-carboxylate dehydrogenase results in type II
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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
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at time but often involves seizures, convulsions and intellectual
disability.
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Catabolism of Tryptophan to -KetoadipateFig 29.16. Harper's Illustrated Biochemistry 30th Edition
Disorder related to Tryptophan
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Hartnup disease: In catabolism of Typ, kynureninase requiresPLP (active form of vit B6), acts on 3-L hydroxylkynurenine
? Defect in kynureninase limits tryptophan availability for niacin
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biosynthesis, cause reduced synthesis of NAD+ and NADP+
leads to pellagra-like signs and symptoms.
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? Due to lack of PLP, Kynureninase reaction blocked and 3-Lhydroxylkynurenine is diverted and form xanthurenate catalyzed
by Kynurenine transferases
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Cont--
? Elevated levels of xanthurenate shows vit B6 deficiency
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? Hartnup disease reflects impaired intestinal and renal transportof tryptophan and other neutral aa
? Indole derivatives of unabsorbed tryptophan formed by
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intestinal bacteria are excreted
Catabolic pathways of seven aa to Acetyl-CoA
Threonine yield some acetyl CoA also
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Fig18.21: Lehninger Principles of Biochemistry by David L Nelson
Disorder related to Lysine
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? Genetic defect in saccharopine dehydrogenase that catalyzeslysine into saccharopine results in hyperlysinemia and
hyperlysinuria (elevated levels of lysine in the blood and urine,
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respectively) along with mental and physical retardation.
Group Discussion
? Subtopics of previous class discussed in groups.
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Thank you