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Titolo:
Study of the structure-activity relationships for the pyrazinamidase (PncA) from Mycobacterium tuberculosis
Autore:
Lemaitre, N; Callebaut, I; Frenois, F; Jarlier, V; Sougakoff, W;
Indirizzi:
Univ Paris 06, Lab Rech Mol Antibiot, Fac Med Pitie Salpetriere, F-75634 Paris 13, France Univ Paris 06 Paris France 13 itie Salpetriere, F-75634 Paris 13, France Univ Paris 06, LMCP, CNRS UMR C7590, F-75252 Paris, France Univ Paris 06 Paris France F-75252 CNRS UMR C7590, F-75252 Paris, France Univ Paris 07, LMCP, CNRS UMR C7590, F-75252 Paris 05, France Univ Paris 07 Paris France 05 , CNRS UMR C7590, F-75252 Paris 05, France BioXtal, Pepiniere Entreprises GIF, F-91193 Gif Sur Yvette, France BioXtal Gif Sur Yvette France F-91193 IF, F-91193 Gif Sur Yvette, France
Titolo Testata:
BIOCHEMICAL JOURNAL
, volume: 353, anno: 2001,
parte:, 3
pagine: 453 - 458
SICI:
0264-6021(20010201)353:<453:SOTSRF>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
N-CARBAMOYLSARCOSINE AMIDOHYDROLASE; HYDROPHOBIC CLUSTER-ANALYSIS; CRYSTAL-STRUCTURE; ARTHROBACTER SP; MUTATIONS; RESISTANCE;
Keywords:
amidohydrolase; homology modelling; hydrophobic cluster analysis; pyrazinamide;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
20
Recensione:
Indirizzi per estratti:
Indirizzo: Sougakoff, W Univ Paris 06, Lab Rech Mol Antibiot, Fac Med Pitie Salpetriere, 91 Bvd Hop, F-75634 Paris 13, France Univ Paris 06 91 Bvd Hop Paris France 13 34 Paris 13, France
Citazione:
N. Lemaitre et al., "Study of the structure-activity relationships for the pyrazinamidase (PncA) from Mycobacterium tuberculosis", BIOCHEM J, 353, 2001, pp. 453-458

Abstract

In an attempt to investigate the molecular basis of pyrazinamide hydrolysis by the PncA protein from Mycobacterium tuberculosis, we determined the pyrazinamidase activity of nine PncA mutants bearing a single amino acid substitution. Among them, three mutants (D8G, K96T and S104R) had virtually no activity (less than or equal to 0.004 unit/mg), five (F13S, T61P, P69L, Y103S and A146V) retained a low level of activity (0.06-0.25 unit/mg) and one (T167L) exhibited a wild-type activity (1.51 units/mg). The possible structural effects of these substitutions were assessed by analysing a three-dimensional model of the PncA protein constructed on the basis of the crystal structure of the N-carbamoylsarcosine amidohydrolase (CSHase) from Arthrobacter sp.. an amidohydrolase which was found by hydrophobic cluster analysis to be closely related to PncA, In the PncA model, five of the mutated residues, Asp-8, Phe-13, Lys-96, Tyr-103 and Ser-104, were located within a 6 Angstrom sphere around the cysteine residue Cys-138, which could be the counterpart of the active cysteine residue Cys-177 found in the CSHase. Among the remaining mutated residues, Thr-61, Pro-69 and Ala-146 were found to be more distant from Cys-138 but were associated with structural elements contributing to the catalytic centre, whereas Thr-167 was situated in an alpha -helix located far from the putative active site. These data suggest that the decrease in pyrazinamidase activity observed in the PncA mutant proteins is well correlated with the structural modifications the mutations can cause in the environment of the putative active cysteine Cys-138.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/01/20 alle ore 07:31:31