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Titolo:
Specificity of inhibition of matrix metalloproteinase activity by doxycycline - Relationship to structure of the enzyme
Autore:
Smith, GN; Mickler, EA; Hasty, KA; Brandt, KD;
Indirizzi:
Indiana Univ, Sch Med, Div Rheumatol, Indianapolis, IN 46202 USA Indiana Univ Indianapolis IN USA 46202 umatol, Indianapolis, IN 46202 USA Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA Univ Tennessee Memphis TN USA 38163 , Ctr Hlth Sci, Memphis, TN 38163 USA
Titolo Testata:
ARTHRITIS AND RHEUMATISM
fascicolo: 6, volume: 42, anno: 1999,
pagine: 1140 - 1146
SICI:
0004-3591(199906)42:6<1140:SOIOMM>2.0.ZU;2-N
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN FIBROBLAST COLLAGENASE; HUMAN OSTEOARTHRITIC CARTILAGE; HUMAN NEUTROPHIL COLLAGENASE; C-TERMINAL DOMAIN; TETRACYCLINE INHIBITION; COLLAGENOLYTIC ACTIVITY; PERIODONTAL-DISEASES; CATALYTIC DOMAIN; PROCOLLAGENASE; PURIFICATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Smith, GN IndianaNUniv, Sch Med, Div Rheumatol, 541 Clin Dr,Room 492, Indianapolis, I Indiana Univ 541 Clin Dr,Room 492 Indianapolis IN USA 46202 s, I
Citazione:
G.N. Smith et al., "Specificity of inhibition of matrix metalloproteinase activity by doxycycline - Relationship to structure of the enzyme", ARTH RHEUM, 42(6), 1999, pp. 1140-1146

Abstract

Objective. To investigate the inhibition of matrix metalloproteinase 1 (MMP-1), MMP-8, and MMP-13 by doxycycline, and to determine whether the variable hemopexin-like domain of each MMP was responsible for the differences insusceptibility to doxycycline inhibition among these collagenases,Methods. Recombinant human MMP-1 (collagenase 1), MMP-8 (collagenase 2), and MMP-13 (collagenase 3), truncated forms of MMP-8 and MMP-13 lacking the hemopexin-like domain, and a mutant form of truncated MMP-13 were used in these studies. The activity of the full-length MMP in the presence of doxycycline was tested against type II collagen, a natural substrate for the enzymes. A small peptolide substrate was used to determine which structural features of the MMPs were related to sensitivity to doxycycline inhibition. Results. The activity of MMP-13 and MMP-8 against type II collagen was inhibited by 50-60% by 30 mu M doxycycline, while that of MMP-1 was inhibited only 18% by 50 mu M doxycycline. In contrast, in experiments with the peptolide substrate, neither full-length nor truncated MMP-13 was inhibited until the concentration of the drug exceeded 90 mu M. MMP-8 and truncated MMP-8were sensitive to inhibition by 30 mu M doxycycline, while MMP-1 was slightly inhibited (14%) by 90 mu M doxycycline, For MMP-8, inhibition was reversible upon dilution and was independent of the order in which the reagents were added. Kinetic analysis of the inhibition constant (K-i) of MMP-8 (K-i= 36 mu M) and truncated MMP-8 (K-i = 77 mu M) indicated that inhibition was noncompetitive,Conclusion. Significant inhibition of MMP-13 and MMP-8 activity against collagen occurred in vitro at concentrations that were near the concentrations achieved in serum after oral dosing. Studies with truncated enzymes and 2substrates suggest that doxycycline disrupts the conformation of the hemopexin-like domain of MMP-13 and the catalytic domain of MMP-8.

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Documento generato il 05/07/20 alle ore 00:36:19