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Mitochondrial Oxidation of Fatty Acids and Several Amino Acids
The mitochondrial oxidation of fatty acids and several amino acids involves oxidation of acyl-CoA thiolesters to the corresponding 2,3-enoyl-CoA thiolesters by a group of structurally related acyl-CoA dehydrogenases. These flavoprotein dehydrogenases are reoxidized by a dimeric flavoprotein, electron transfer flavoprotein (ETF). Selected Publications
Simkovic M, Degala GD, Eaton SS, Frerman FE. Expression of human electron transfer flavoprotein-ubiquinone oxidoreductase from a baculovirus vector: kinetic and spectral characterization of the human protein. Biochem J. 2002 Jun 15;364(Pt 3):659-67 Rao KS, Vander Velde D, Dwyer TM, Goodman SI, Frerman FE. Alternate substrates of human glutaryl-CoA dehydrogenase: structure and reactivity of substrates, and identification of a novel 2-enoyl-CoA product. Biochemistry. 2002 Jan 29;41(4):1274-84. Chisholm CA, Vavelidis F, Lovell MA, Sweetman L, Roe CR, Roe DS, Frerman FE, Wilson WG. Prenatal diagnosis of multiple acyl-CoA dehydrogenase deficiency: association with elevated alpha-fetoprotein and cystic renal changes. Prenat Diagn. 2001 Oct;21(10):856-9. Westover JB, Goodman SI, Frerman FE. Binding, hydration, and decarboxylation of the reaction intermediate glutaconyl-coenzyme A by human glutaryl-CoA dehydrogenase. Biochemistry. 2001 Nov 20;40(46):14106-14. Chohan KK, Jones M, Grossmann JG, Frerman FE, Scrutton NS, Sutcliffe MJ. Protein dynamics enhance electronic coupling in electron transfer complexes. J Biol Chem. 2001 Sep 7;276(36):34142-7. |
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This protein contains a single FAD prosthetic group and a single equivalent of 5'-adenosine monophosphate which is essential for the in vitro folding fof the protein. ETF is located in the mitochondria matrix and transfers electrons to the intrinsic membrane protein, electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). ETF-QO is the reductant of the ubiquinone which is oxidized by the cytochrome bc1 complex of the main respiratory chain. Inherited defects in ETF and ETF-QO cause glutaric acidemia type II, an often fatal inborn error of metabolism. The laboratory has over expressed and crystallized wild ETF and ETF-QO, and several mutant forms of ETF. This has permitted the investigation of the biochemical bases of several forms of the inherited disease. Recent investigations focus on the role(s) of amino acids that contact the flavin of ETF and modulate the chemistry of ETF and its interaction with primary flavoprotein dehydrogenases and ETF-QO. We are also employing several flavin analogs (4'deoxyFAD, 4'(amino)FAD and 1-deazaFAD) to investigate the role of a novel hydrogen bond between the 4' hydroxyl of the ribityl side chain fo FAD and nitrogen 1 of the flavin ring. This hydrogen bond appears to modulate the oxidation-reduction potential of the flavin, and may provide a route for electron transfer out of the ETF flavin into the flavin of ETF-QO. Finally, we are expressing several other mutations found in patients' ETF to understand the effects of these mutation on the structure and oxidation-reduction potential and resulting effects on electron transfer through the protein.