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Pyruvate formate lyase
Additional recommended knowledge
Pyruvate formate lyase (PFL) (EC 188.8.131.52) is an important enzyme (found in Escherichia coli and other organisms) that helps regulate anaerobic glucose metabolism. Using radical chemistry, it catalyzes the reversible conversion of pyruvate and coenzyme-A into formate and acetyl-CoA. The reaction occurs as follows:
Pyruvate formate lyase is a homodimer made of 85 kDa, 759-residue subunits. It has a 10-stranded beta/alpha barrel motif into which is inserted a beta finger that contains major catalytic residues. The active site of the enzyme, elucidated by x-ray crystallography, holds three essential amino acids that perform catalysis (Gly734, Cys418, and Cys419), three major residues that hold the substrate pyruvate close by (Arg435, Arg176, and Ala272), and two flanking hydrophobic residues (Trp333 and Phe432).
Studies have found structural similarities between the active site of pyruvate formate lyase and that of Class I and Class III ribonucleotide reductase (RNR) enzymes.[1,4]
Roles of the 3 Catalytic Residues
Note that each step is reversible.[2,6]
Two additional enzymes regulate the “on” and “off” states of pyruvate formate lyase to regulate anaerobic glucose metabolism: PFL activase (AE) and PFL deactivase (DA). Activated pyruvate formate lyase allows formation of acetyl-CoA, a small molecule important in the production of energy, when pyruvate is available. Deactivated pyruvate formate lyase, even with substrates present, does not catalyze the reaction.
PFL activase is part of the radical SAM (S-adenosylmethionine) superfamily. The enzyme turns pyruvate formate lyase “on” by converting Gly734 (G-H) into a Gly734 radical (G*) via a 5'-deoxyadenosyl radical (radical SAM).
For more information about radical SAM activation and radical SAM enzymes, see the discussion by Wang et al., 2007.
PFL deactivase (DA) turns pyruvate formate lyase “off” by quenching the Gly734 radical. Furthermore, pyruvate formate lyase is sensitive to molecular oxygen (O2), the presence of which shuts the enzyme off.
 Becker A. , Fritz-Wolf K. , Kabsch W. , Knappe J. , Schultz S. , Volker wagner A.F. Structure and mechanism of the glycyl radical enzyme pyruvate formate-lyase. 1999 Nat. Struct. Biol. 6: 969-975.
 Becker, A., Kabsch W. X-ray structure of pyruvate formate-lyase in complex with pyruvate and CoA. How the enzyme uses the Cys-418 thiyl radical for pyruvate cleavage. 2002 J Biol Chem. 277(42): 40036-42.
 Frey, M., Rothe, M., Wagner, AF., Knappe, J. Adenosylmethionine-dependent synthesis of the glycyl radical in pyruvate formate-lyase by abstraction of the glycine C-2 pro-S hydrogen atom. Studies of [2H]glycine-substituted enzyme and peptides homologous to the glycine 734 site. 1994 J Biol Chem. 269(17):12432-7.
 Leppanen V.M. , Merckel M.C. , Ollis D.L. , Wong K.K. , Kozarich J.W. , Goldman A. Pyruvate formate lyase is structurally homologous to type I ribonucleotide reductase. 1999 Structure 7: 733-744.
 Nnyepi, MR., Peng, Y., Broderick, JB. Inactivation of E. coli pyruvate formate-lyase: role of AdhE and small molecules. 2007 Arch Biochem Biophys. 459(1):1-9.
 Plaga, W., Wielhaber, G., Wallach, J., Knappe, J. Modification of Cys-418 of pyruvate formate-lyase by methacrylic acid, based on its radical mechanism. 2000 FEBS Lett. 466(1): 45-8.
 Wang, SC., Frey PA. S-adenosylmethionine as an oxidant: the radical SAM superfamily. 2007 Trends Biochem Sci. 32(3): 101-10.
 Zhang, W., Wong, KK., Magliozzo, RS., Kozarich, JW. Inactivation of pyruvate formate-lyase by dioxygen: defining the mechanistic interplay of glycine 734 and cysteine 419 by rapid freeze-quench EPR. 2001 Biochemistry 40(13): 4123-30.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Pyruvate_formate_lyase". A list of authors is available in Wikipedia.|