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Titolo:
Crystal structure of macrophage migration inhibitory factor-complexed with(E)-2-fluoro-p-bydroxycinnamate at 1.8 angstrom resolution: Implications for enzymatic catalysis and inhibition
Autore:
Taylor, AB; Johnson, WH; Czerwinski, RM; Li, HS; Hackert, ML; Whitman, CP;
Indirizzi:
Univ Texas, Coll Pharm, Dept Chem & Biochem, Austin, TX 78712 USA Univ Texas Austin TX USA 78712 Dept Chem & Biochem, Austin, TX 78712 USA Univ Texas, Coll Pharm, Div Med Chem, Austin, TX 78712 USA Univ Texas Austin TX USA 78712 Pharm, Div Med Chem, Austin, TX 78712 USA
Titolo Testata:
BIOCHEMISTRY
fascicolo: 23, volume: 38, anno: 1999,
pagine: 7444 - 7452
SICI:
0006-2960(19990608)38:23<7444:CSOMMI>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
AMINO-TERMINAL PROLINE; 4-OXALOCROTONATE TAUTOMERASE; PHENYLPYRUVATE TAUTOMERASE; FACTOR MIF; REFINEMENT; KETONIZATION; MECHANISM; ISOMERASE; CYTOKINE; 2-HYDROXYMUCONATE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Hackert, ML Univ Texas, Coll Pharm, Dept Chem & Biochem, Austin, TX 78712 USA Univ Texas Austin TX USA 78712 Biochem, Austin, TX 78712 USA
Citazione:
A.B. Taylor et al., "Crystal structure of macrophage migration inhibitory factor-complexed with(E)-2-fluoro-p-bydroxycinnamate at 1.8 angstrom resolution: Implications for enzymatic catalysis and inhibition", BIOCHEM, 38(23), 1999, pp. 7444-7452

Abstract

Macrophage migration inhibitory facto; (MIF) exhibits dual activities. It acts as an immunoregulatory protein as Well as a phenylpyruvate tautomerase. To understand better the relationship between these two activities and toelucidate the structural basis for the enzymatic activity, a crystal structure of a complex between murine MIF and (E)-2-fluoro-p-hydroxycinnamate, acompetitive inhibitor of the tautomerase activity, has been determined to 1.8 Angstrom resolution. The structure is nearly superimposable on that of the free protein indicating that the presence of the inhibitor does not result in any major structural changes. The inhibitor also confirms the location of the,active site in a hydrophobic cavity containing the amino-terminalproline. Within this cavity, the inhibitor interacts with residues from adjacent subunits. At the back of the cavity, the side-chain carbonyl oxygen of Asn-97' interacts with the phenolic hydroxyl group of the inhibitor while at the mouth of the cavity the ammonium group of Lys-32 interacts with a carboxylate oxygen. The other carboxylate oxygen of the inhibitor interactswith Pro-1. The hydroxyl group of Tyr-95' interacts,weakly with the fluorogroup on the inhibitor. The hydrophobic side chains of five active-site residues (Met-2, Ile-64, Met-101, Val-106, and Phe-113) and the phenyl moietyof Tyr-95' are responsible for the binding of the phenyl group. Further insight into the enzymatic activity of MIF was obtained by carrying out kinetic studies using the enol isomers of phenylpyruvate and (p-hydroxyphenyl)pyruvate. The results demonstrate that MIF processes the enol isomers more efficiently than the keto isomers primarily because of a decrease in K-m. On the basis of these results, a mechanism is proposed for the MIF-catalyzed tautomerization reaction.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/10/20 alle ore 16:04:30