Branched-chain Amino Acid Metabolon: Interaction of Glutamate Dehydrogenase with the Mitochondrial Branched-chain Aminotransferase (BCATm)

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2009 Oct 28

PMID 19858196

Citations 41

Authors

Mohammad Mainul Islam

Manisha Nautiyal

R Max Wynn

James A Mobley

David T Chuang

Susan M Hutson

Affiliations

Soon will be listed here.

Abstract

The catabolic pathway for branched-chain amino acids includes deamination followed by oxidative decarboxylation of the deaminated product branched-chain alpha-keto acids, catalyzed by the mitochondrial branched-chain aminotransferase (BCATm) and branched-chain alpha-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 alpha-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.

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References

Lynch C, Halle B, Fujii H, Vary T, Wallin R, Damuni Z . Potential role of leucine metabolism in the leucine-signaling pathway involving mTOR. Am J Physiol Endocrinol Metab. 2003; 285(4):E854-63. DOI: 10.1152/ajpendo.00153.2003. View

Suryawan A, Hawes J, Harris R, Shimomura Y, JENKINS A, Hutson S . A molecular model of human branched-chain amino acid metabolism. Am J Clin Nutr. 1998; 68(1):72-81. DOI: 10.1093/ajcn/68.1.72. View

An S, Kumar R, Sheets E, Benkovic S . Reversible compartmentalization of de novo purine biosynthetic complexes in living cells. Science. 2008; 320(5872):103-6. DOI: 10.1126/science.1152241. View

Fang J, Hsu B, MacMullen C, Poncz M, Smith T, Stanley C . Expression, purification and characterization of human glutamate dehydrogenase (GDH) allosteric regulatory mutations. Biochem J. 2002; 363(Pt 1):81-7. PMC: 1222454. DOI: 10.1042/0264-6021:3630081. View

Sweatt A, Wood M, Suryawan A, Wallin R, Willingham M, Hutson S . Branched-chain amino acid catabolism: unique segregation of pathway enzymes in organ systems and peripheral nerves. Am J Physiol Endocrinol Metab. 2003; 286(1):E64-76. DOI: 10.1152/ajpendo.00276.2003. View

Sener A, Malaisse W . L-leucine and a nonmetabolized analogue activate pancreatic islet glutamate dehydrogenase. Nature. 1980; 288(5787):187-9. DOI: 10.1038/288187a0. View

SRERE P . Macromolecular interactions: tracing the roots. Trends Biochem Sci. 2000; 25(3):150-3. DOI: 10.1016/s0968-0004(00)01550-4. View

Davoodi J, Drown P, Bledsoe R, Wallin R, Reinhart G, Hutson S . Overexpression and characterization of the human mitochondrial and cytosolic branched-chain aminotransferases. J Biol Chem. 1998; 273(9):4982-9. DOI: 10.1074/jbc.273.9.4982. View

Gylfe E . Comparison of the effects of leucines, non-metabolizable leucine analogues and other insulin secretagogues on the activity of glutamate dehydrogenase. Acta Diabetol Lat. 1976; 13(1-2):20-4. DOI: 10.1007/BF02591577. View

10.

Hutson S . Branched chain alpha-keto acid oxidative decarboxylation in skeletal muscle mitochondria. Effect of isolation procedure and mitochondrial delta pH. J Biol Chem. 1986; 261(10):4420-5. View

11.

Stanley C, Lieu Y, Hsu B, Burlina A, Greenberg C, Hopwood N . Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med. 1998; 338(19):1352-7. DOI: 10.1056/NEJM199805073381904. View

12.

MacDonald M, Hasan N, Longacre M . Studies with leucine, beta-hydroxybutyrate and ATP citrate lyase-deficient beta cells support the acetoacetate pathway of insulin secretion. Biochim Biophys Acta. 2008; 1780(7-8):966-72. PMC: 2756157. DOI: 10.1016/j.bbagen.2008.03.017. View

13.

Chuang J, Davie J, Wynn R, Chuang D . Production of recombinant mammalian holo-E2 and E3 and reconstitution of functional branched-chain alpha-keto acid dehydrogenase complex with recombinant E1. Methods Enzymol. 2000; 324:192-200. DOI: 10.1016/s0076-6879(00)24231-6. View

14.

Gao Z, Young R, Li G, Najafi H, Buettger C, Sukumvanich S . Distinguishing features of leucine and alpha-ketoisocaproate sensing in pancreatic beta-cells. Endocrinology. 2003; 144(5):1949-57. DOI: 10.1210/en.2002-0072. View

15.

Newsholme P, Brennan L, Rubi B, Maechler P . New insights into amino acid metabolism, beta-cell function and diabetes. Clin Sci (Lond). 2004; 108(3):185-94. DOI: 10.1042/CS20040290. View

16.

Yennawar N, Dunbar J, Conway M, Hutson S, Farber G . The structure of human mitochondrial branched-chain aminotransferase. Acta Crystallogr D Biol Crystallogr. 2001; 57(Pt 4):506-15. DOI: 10.1107/s0907444901001925. View

17.

Hutton J, Sener A, Malaisse W . Interaction of branched chain amino acids and keto acids upon pancreatic islet metabolism and insulin secretion. J Biol Chem. 1980; 255(15):7340-6. View

18.

Yennawar N, Islam M, Conway M, Wallin R, Hutson S . Human mitochondrial branched chain aminotransferase isozyme: structural role of the CXXC center in catalysis. J Biol Chem. 2006; 281(51):39660-71. DOI: 10.1074/jbc.M607552200. View

19.

Islam M, Wallin R, Wynn R, Conway M, Fujii H, Mobley J . A novel branched-chain amino acid metabolon. Protein-protein interactions in a supramolecular complex. J Biol Chem. 2007; 282(16):11893-903. DOI: 10.1074/jbc.M700198200. View

20.

Yennawar N, Conway M, Yennawar H, Farber G, Hutson S . Crystal structures of human mitochondrial branched chain aminotransferase reaction intermediates: ketimine and pyridoxamine phosphate forms. Biochemistry. 2002; 41(39):11592-601. DOI: 10.1021/bi020221c. View