Branched-chain amino acid metabolon

Interaction of glutamate dehydrogenase with the mitochondrial branched-chain aminotransferase (BCATm)

Mohammad Mainul Islam, Manisha Nautiyal, R. Max Wynn, James A. Mobley, David T. Chuang, Susan M. Hutson

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

The catabolic pathway for branched-chain amino acids includes deamination followed by oxidative decarboxylation of the deaminated product branched-chain α-keto acids, catalyzed by the mitochondrial branched-chain aminotransferase (BCATm) and branched-chain α-keto acid dehydrogenase enzyme complex (BCKDC). We found that BCATm binds to the E1 decarboxylase of BCKDC, forming a metabolon that allows channeling of branched-chain α-keto acids from BCATm to E1. The protein complex also contains glutamate dehydrogenase (GDH1), 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1, pyruvate carboxylase, and BCKDC kinase. GDH1 binds to the pyridoxamine 5′-phosphate (PMP) form of BCATm (PMP-BCATm) but not to the pyridoxal 5′-phosphate-BCATm and other metabolon proteins. Leucine activates GDH1, and oxidative deamination of glutamate is increased further by addition of PMP-BCATm. Isoleucine and valine are not allosteric activators of GDH1, but in the presence of 5′-phosphate-BCATm, they convert BCATm to PMP-BCATm, stimulating GDH1 activity. Sensitivity to ADP activation of GDH1 was unaffected by PMP-BCATm; however, addition of a 3 or higher molar ratio of PMP-BCATm to GDH1 protected GDH1 from GTP inhibition by 50%. Kinetic results suggest that GDH1 facilitates regeneration of the form of BCATm that binds to E1 decarboxylase of the BCKDC, promotes metabolon formation, branched-chain amino acid oxidation, and cycling of nitrogen through glutamate.

Original languageEnglish (US)
Pages (from-to)265-276
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number1
DOIs
StatePublished - Jan 1 2010

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Branched Chain Amino Acids
Glutamate Dehydrogenase
Pyridoxamine
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
Phosphates
Keto Acids
Deamination
Carboxy-Lyases
Enzymes
Glutamic Acid
Synaptosomal-Associated Protein 25
4-Nitrophenylphosphatase
Pyruvate Carboxylase
Decarboxylation
Pyridoxal Phosphate
Isoleucine
Valine
Guanosine Triphosphate
Proteins
Leucine

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Branched-chain amino acid metabolon : Interaction of glutamate dehydrogenase with the mitochondrial branched-chain aminotransferase (BCATm). / Islam, Mohammad Mainul; Nautiyal, Manisha; Wynn, R. Max; Mobley, James A.; Chuang, David T.; Hutson, Susan M.

In: Journal of Biological Chemistry, Vol. 285, No. 1, 01.01.2010, p. 265-276.

Research output: Contribution to journalArticle

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