FDH: an aldehyde dehydrogenase fusion enzyme in folate metabolism.
FDH (10-formyltetrahydrofolate dehydrogenase, Aldh1L1, EC 1.5.1.6) converts 10-formyltetrahydrofolate (10-formyl-THF) to tetrahydrofolate and CO(2) in a NADP(+)-dependent reaction. It is a tetramer of four identical 902 amino acid residue subunits. The protein subunit is a product of a natural fusion of three unrelated genes and consists of three distinct domains. The N-terminal domain of FDH (residues 1-310) carries the folate binding site and shares sequence homology and structural topology with other enzymes utilizing 10-formyl-THF as a substrate. In vitro it functions as 10-formyl-THF hydrolase, and evidence indicate that this activity is a part of the overall FDH mechanism. The C-terminal domain of FDH (residues 400-902) originated from an aldehyde dehydrogenase-related gene and is capable of oxidation of short-chain aldehydes to corresponding acids. Similar to classes 1 and 2 aldehyde dehydrogenases, this domain exists as a tetramer and defines the oligomeric structure of the full-length enzyme. The two catalytic domains are connected by an intermediate linker (residues 311-399), which is a structural and functional homolog of carrier proteins possessing a 4'-phosphopantetheine prosthetic group. In the FDH mechanism, the intermediate linker domain transfers a formyl, covalently attached to the sulfhydryl group of the phosphopantetheine arm, from the N-terminal domain to the C-terminal domain. The overall FDH mechanism is a coupling of two sequential reactions, a hydrolase and a formyl dehydrogenase, bridged by a substrate transfer step. In this mechanism, one domain provides the folate binding site and a hydrolase catalytic center to remove the formyl group from the folate substrate, another provides a transfer vehicle between catalytic centers and the third one contributes the dehydrogenase machinery further oxidizing formyl to CO(2).
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, United States. Krupenko@musc.edu
Sergey A
SA
Krupenko
D000444:Aldehyde Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D055162:Biocatalysis; D020134:Catalytic Domain; D003067:Coenzymes / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism*; D008958:Models, Molecular; D009536:Niacinamide / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D003067:Coenzymes; D011993:Recombinant Fusion Proteins; D009536:Niacinamide; D005492:Folic Acid; D000444:Aldehyde Dehydrogenase; D003545:Cysteine