Download MBBS Biochemistry PPT 41 Catabolism Of Carbon Skeletons Lecture Notes

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Department of Biochemistry

Specific Learning Objectives

Catabolism of Carbon Skeletons of aa and related disorders:

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Distinguish following disease states associated with Inborn Errors of Metabolism, including

deficient enzyme, relation of deficiency to build-up of secondary metabolites, and clinically relevant

information related to disease state (vitamin deficiencies, symptoms, diagnosis, pathology and

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treatments:

? Cystinuria
? Histidinemia

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? Phenylketonuria (PKU)
? Methylmalonyl CoA mutase deficiency e. Albinism
? Homocystinuria
? Alkaptonuria
? Maple syrup urine disease

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? Cystathioninuria
? Tyrosinemia
Catabolism of Phenylalanine and Tyrosine with genetic disorders
Catabolic pathways of five aa to -ketoglutarate and associated disorders
Summary of Amino acid Catabolism

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

Genetic disorders related to Amino-acid catabolism

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Table 18.2: Lehninger Principles of Biochemistry by David L Nelson
Catabolism of Phenylalanine and Tyrosine with genetic disorders

Homogentisate Oxidase/

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Neonatal Tyrosinemia or

Or p-hydroxyphenylpyruvate hydroxylase

Fig18.23: Lehninger Principles of Biochemistry by David L Nelson

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Alternative pathways for catabolism of phenylalanine in PKU

? Phenylalanine and phenylpyruvate accumulate in

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blood and tissues and are excreted in urine--hence

name "phenylketonuria"

? Phenylpyruvate, excreted as either decarboxylated

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to phenylacetate or reduced to phenyllactate

? Phenylacetate gives a characteristic odor to urine,

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(for detection of PKU in infants)

Fig18.25: Lehninger Principles of Biochemistry by David L Nelson, 6th Ed.
Disorder related to phenylalanine catabolism

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Phenylketonuria (PKU): Genetic defect in phenylalanine hydroxylase, first

enzyme in catabolic pathway for phenylalanine, is responsible for PKU, most

common cause of elevated levels of phenylalanine (hyperphenylalaninemia)

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Excess phenylalanine is transaminated to Phenylpyruvate

The "spil over" of Phenylpyruvate (a phenylketone) into urine

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High concentration of phenylalanine itself gives rise to brain dysfunction.

Cont--

Phenylalanine hydroxylase requires cofactor tetrahydrobiopterin,

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which carries electrons from NADH to O2 and becomes oxidized to

dihydrobiopterin

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It is subsequently reduced by enzyme dihydrobiopterin reductase in

a reaction that requires NADH

Diet low in phenylalanine can prevent mental retardation of PKU

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Disorder related to Tyrosine catabolism

Alkaptonuria: Metabolic defect in alkaptonuria is a defective homogentisate

oxidase the enzyme that catalyzes homogentisate to Maleylacetoacetate

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Large amounts of homogentisate are excreted and urine darkens on

exposure to air due to oxidation of excreted homogentisate

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This autooxidizes to the corresponding quinone, which polymerizes to

form an intensely dark color

Late in disease, there is arthritis and connective tissue pigmentation

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(ochronosis) due to oxidation of homogentisate to benzoquinone acetate,

which polymerizes and binds to connective tissue

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Type I Tyrosinemia

Several metabolic disorders are associated with tyrosine catabolic

pathway

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Probable metabolic defect in type I tyrosinemia (tyrosinosis) is at

fumarylacetoacetate hydrolase
Untreated acute and chronic tyrosinosis leads to death from liver

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failure, renal tubular dysfunction, rickets and polyneuropathy

Type II Tyrosinemia

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Alternate metabolites of tyrosine are also excreted in type II

tyrosinemia (Richner-Hanhart syndrome), a defect in tyrosine

aminotransferase produces accumulation and excretion of tyrosine

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and metabolites

Leads to eye and skin lesions and mental retardation

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Type III Tyrosinemia

Neonatal Tyrosinemia or type III tyrosinemia, due to lowered activity of p-

hydroxyphenylpyruvate

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dioxygenase/

p-hydroxyphenylpyruvate

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hydroxylase

It can cause learning problems, seizures, and loss of balance

Therapy employs a diet low in protein, tyrosine and phenylalanine

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Catabolic pathways of five aa to -ketoglutarate

Proline dehydrogenase/

1-pyrroline-5-carboxylate dehydrogenase/

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Fig18.26: Lehninger Principles of Biochemistry by David L Nelson

Disorder related to Proline catabolism

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Type I hyperprolinemia

Metabolic block in type I hyperprolinemia is at proline

dehydrogenase/proline oxidase

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Some individuals with hyperprolinemia type I exhibit seizures,

intellectual disability, or other neurological or psychiatric problems
Type II hyperprolinemia

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Metabolic block in type II hyperprolinemia is at 1-pyrroline-5-

carboxylate dehydrogenase, which also participates in catabolism of

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arginine, ornithine, and hydroxyproline

It leads to seizures or intellectual disability.

Two Clinical-cases discussed

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Reference Books

17

1) Lehninger Principles of Biochemistry, 6th Ed.

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2) Harper's Il ustrated Biochemistry, 30th edition
3) Biochemistry, Lippincott's Il ustrated Reviews, 6th Ed

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