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BRANCHED CHAIN AMINO ACID METABOLISM

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BRANCHED CHAIN AMINO ACID METABOLISM

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BRANCHED CHAIN AMINO ACID METABOLISM

  1. 1.  Valine, Ieucine & isoleucine are the branched chain & essential amino acids.  Valine (Val) is glucogenic amino acid.  Leucine (Leu) is ketogenic amino acid.  Isoleucine (Ile) is both ketogenic & glucogenic amino acid.
  2. 2.  These amino acids serve as an alternate source of fuel for the brain especially under conditions of starvation.  The first three metabolic reactions are common to the branched chain amino acids. 1. Transamination 2. Oxidative decarboxylation 3. Dehydrogenation
  3. 3.  Transamination:  The three amino acids undergo a reversible transamination to form their respective keto acids.  Oxidative decarboxylation:  α-Keto acid dehydrogenase is a complex mitochondrial enzyme.
  4. 4.  It is comparable in function to PDH complex & requires 5 coenzymes - TPP, lipoamide, FAD, coenzyme A & NAD+.  α-Keto acid dehydrogenase catalyses oxidative decarboxylation of the keto acids to the corresponding acyl CoA thioesters.  This is a regulatory enzyme.
  5. 5.  Dehydrogenation:  The dehydrogenation is similar to that in fatty acid oxidation.  FAD is the coenzyme & there is an incorporation of a double bond.  There are two enzymes responsible for dehydrogenation.  The branched chain amino acids diverges & takes independent routes.
  6. 6.  Valine is converted to propionyl CoA, a precursor for glucose.  Leucine produces acetyl CoA & acetoacetate, the substrates for fatty acid synthesis.  Isoleucine is degraded to propionyl CoA & acetyl CoA.  Valine is glycogenic & leucine is ketogenic.  Isoleucine is both glycogenic & ketogenic.
  7. 7. Valine, Leucine, Isoleucine Corresponding α-ketoacids (α-ketoisovalerate, α-ketoisocaproate, α-keto β-methyl valerate) Corresponding α, β-unsaturated acyl CoA thioesters (Isobutyryl CoA, Isovaleryl CoA, α-methylbutyryl CoA) Branched chain amino acid transaminase α-Ketoacid dehydrognase NAD+, CoASH NADH, CoA
  8. 8. β-Methylcrotonyl CoA Acyl CoA Dehydrogenase FAD FADH2 Methylacrylyl CoA Triglyl CoA HMG CoA Acetoacetate Fat Acetyl CoA Propionyl CoA Methylmalonyl CoA Glucose Methylacetoacetyl CoA Propionyl CoA Glucose Acetyl CoA Fat
  9. 9.  Maple syrup urine disease:  The urine of the affected individuals smells like maple syrup or burnt sugar.  Enzyme defect: Branched chain α-keto acid dehydrogenase.
  10. 10.  This causes a blockade in the conversion of α-keto acids to the respective acyl CoA thioesters.  The plasma & urine concentrations of branched amino acids & their keto acids are highly elevated.  This disease is also known as branched chain ketonuria.
  11. 11.  Accumulation of branched chain amino acids causes an impairment in transport & function of other amino acids.  Protein biosynthesis is reduced.  Branched chain amino acids competitively inhibit glutamate dehydrogenase.  The disease results in acidosis, lethargy, convulsions, mental retardation, coma & death within one year after birth.
  12. 12.  Diagnosis:  Urine contains branched chain keto acids, valine, leucine & isoleucine.  Rothera's test is positive.  Diagnosis depends on enzyme analysis.  Diagnosis should be done prior to 1 week after birth.  Treatment:  Diet low in branched chain amino acids.
  13. 13.  This is a less severe variant form of maple syrup urine disease.  Enzyme defect:α-keto acid dehydrogenase.  There is an impairment & no total blockade in the conversion of α-keto acids to their respective acyl CoA thioesters.  Careful diet planning is adequate.
  14. 14.  This is a specific inborn error of leucine metabolism.  Enzyme defect: Enzyme isovaleryl CoA dehydrogenase.  The conversion of isovaleryl CoA to methylcrotonyl CoA is impaired.
  15. 15.  The excretion of isovalerate is high in urine.  The affected individuals exhibit a 'cheesy' odor in the breath & body fluids.  The symptoms include acidosis & mild mental retardation.
  16. 16.  This inborn error is characterized by increased plasma concentration of valine while leucine & isoleucine levels remain normal.  The transamination of valine alone is selectively impaired.
  17. 17.  Textbook of Biochemistry-U Satyanarayana  Textbook of Biochemistry-DM Vasudevan

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