Download MBBS Biochemistry PPT 40 Catabolism Of Carbon Skeletons Of Amino Iii Lecture Notes

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Specific Learning Objectives

Integrate aa synthesis with specific precursors from glycolysis, citric acid

cycle and pentose phosphate pathway

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List which aa are precursors to citric acid cycle intermediates and identify

specific intermediates (in addition to Acetyl-CoA and Acetoacetyl-CoA)

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Catabolic pathways of seven aa to Acetyl-CoA
Summary of Amino acid Catabolism

Fig18.15: Lehninger Principles of Biochemistry by David L Nelson

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Introduction

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

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Cont--

These products directly enter pathways of intermediary metabolism:
Resulting either in synthesis of glucose or lipid or in production of

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energy through their oxidation to CO2 and water by citric acid cycle

Catabolic 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:

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

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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

group is released as ammonia

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

protein shared by and known as E3 in pyruvate dehydrogenase complex

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https://www.slideshare.net/ashokktt/metabolism-of-glycine
Disorder related to glycine

Non-ketotic hyperglycinemia (NKH)

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Humans with serious defects in glycine cleavage system activity due

to absence of one of components of glycine cleavage system

Elevated serum levels of glycine, leading to mental retardation and

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death in very early childhood

Cont--

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In one of glycine degradation pathway, glycine is converted into

glyoxylate by D-amino acid oxidase

Glycine is precursor of glyoxalate, which can be transaminated back to

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glycine or oxidized to oxalate by lactate dehydrogenase

Excessive production of oxalate forms the insoluble calcium oxalate

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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 cysteine

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to be reabsorbed into blood from filtered fluid that wil become urine

Mutations in either of these genes disrupt ability of this transporter protein

exist in kidney tubules to reabsorb these aa, allowing them to excretion of

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these aa in urine
Cystinosis

Cystinosis is a lysosomal storage disease in which abnormal

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accumulation of cystine, leads to intracellular crystal formation throughout

body. Cystine: It is formed from oxidation of two cysteine molecules, via formation of a

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disulfide bond)

Cystinosis is most common cause of Fanconi syndrome in pediatric age

group

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Fanconi syndrome occurs when function of cells in renal tubules is

impaired, leading to abnormal amounts of carbohydrates and amino acids

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in urine, excessive urination, and low blood levels of potassium and

phosphates

Catabolic pathway of Hydroxyproline

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

Type II hyperprolinemia: A defect in 4-hydroxyproline dehydrogenase results

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in hyperhydroxyprolinemia, an excess of free hydroxyproline in plasma and

urine
Associated with mental retardation

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Type II hyperprolinemia: A defect in glutamate--semialdehyde

dehydrogenase/ 1-pyrroline-3-hydroxyl-5-carboxylate dehydrogenase
Type II hyperprolinemia is a rare form of disorder may appear benign at

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time but often involves seizures, convulsions and intellectual disability

Catabolic pathways of seven aa to Acetyl-CoA

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

Tryptophan breakdown is most complex of all pathways of aa

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catabolism in animal tissues

Portions of tryptophan (four of its carbons) yield acetyl-CoA via

acetoacetyl CoA

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Some of intermediates in tryptophan catabolism are precursors for

tsynthesis of other biomolecules, including nicotinate, a precursor of

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NAD and NADP, serotonin

Catabolism of Tryptophan to -Ketoadipate

Fig 29.16. Harper's Illustrated Biochemistry 30th Edition

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Disorder related to Tryptophan

Hartnup disease: In catabolism of Typ, kynureninase requires PLP (active

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

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Defect in kynureninase limits tryptophan availability for niacin

biosynthesis, cause reduced synthesis of NAD+ and NADP+ leads to

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pellagra-like signs and symptoms.

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

hydroxylkynurenine is diverted and form xanthurenate catalyzed by

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Kynurenine transferases

Cont--

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Elevated levels of xanthurenate shows vit B6 deficiency

Hartnup disease reflects impaired intestinal and renal transport of

tryptophan and other neutral aa

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Indole derivatives of unabsorbed tryptophan formed by intestinal

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

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Threonine yield some acetyl CoA also

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

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Saccharopine lysine catabolism pathway

First two steps of saccharopine

pathway are catalysed by bifunctional

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enzyme,-aminoadipic semialdehyde

synthase (AASS), which possess

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both lysine-ketoglutarate reductase

(LKR)

and

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saccharopine

dehydrogenase (SDH) activities

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https://en.wikipedia.org/wiki/Lysine
Disorder related to Lysine

Hyperlysinemia: is an autosomal recessive inborn error of L-lysine degradation in liver

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and production of acetyl-CoA

? lysine and -ketoglutarate are converted into saccharopine by lysine-ketoglutarate

reductase

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? Saccharopine is then oxidized to -aminoadipic semialdehyde and glutamate by

saccharopine dehydrogenase

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Both enzyme activities are catalyzed by a single mitochondrial bifunctional enzyme

named -aminoadipic semialdehyde synthase (AASS) which is encoded by gene

AASS

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One mutation in AASS, cause hyperlysinemia, along with mental and physical

retardation

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Catabolism of Asparagine and Aspartate to Oxaloacetate

Fig18.29: Lehninger Principles of Biochemistry by David L Nelson
Cont--

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L-asparaginase is an effective chemotherapeutic agent in treatment of

cancers that must obtain asparagine from blood, particularly acute

lymphoblastic leukemia

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26

Reference Books

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1) Lehninger Principles of Biochemistry
2) Harper's Il ustrated Biochemistry-30th edition
3) Biochemistry, Lippincott's Il ustrated Reviews, 6th Ed
4) Biochemistry, Donald Voet and Judith G. Voet, 4th Ed.
5) Gregory S. Ducker and Joshua D Rabinowitz. Cel Metab. 2017 Jan 10;25(1):27-

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42
Two Clinical-cases discussed

Thank you

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