INHIBITION OF CLOSTRIDIUM-HISTOLYTICUM COLLAGENASES BY PHOSPHONAMIDE PEPTIDE INHIBITORS

被引:26
作者
DIVE, V [1 ]
YIOTAKIS, A [1 ]
NICOLAOU, A [1 ]
TOMA, F [1 ]
机构
[1] UNIV ATHENS,DEPT ORGAN CHEM,ATHENS,GREECE
来源
EUROPEAN JOURNAL OF BIOCHEMISTRY | 1990年 / 191卷 / 03期
关键词
D O I
10.1111/j.1432-1033.1990.tb19175.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Several phosphonamide peptides having the general structure R‐PO(OH)‐Xaa‐Yaa‐Zaa were synthesized and tested for inhibition of Clostridium histolyticum collagenase. Inhibition was found to depend on the nature of R, Xaa, Yaa and Zaa such that the maximal affinity (Ki= 5 nM) was observed when R =p‐nitrophenylethyl, Xaa = Gly, Yaa = Pro and Zaa = 2‐aminohexanoic acid; this represents the tightest binding of inhibitor reported to date for any bacterial collagenase. Substitution of the p‐nitrophenylethyl by a methyl group led to a 500‐fold decrease of the potency, highlighting the existence of optimal interaction between the nitrophenylethyl side chain and one subsite of the enzyme. Replacement of the NH group in glycine residue (Xaa position) by ‐O‐ or ‐N‐CH3 produces significantly less potent inhibitors, presumably due in part to the loss of a hydrogen bond between the inhibitor and collagenase active site. These phosphonamidates are thought to be acting as transition‐state analogues of the peptide substrate. Copyright © 1990, Wiley Blackwell. All rights reserved
引用
收藏
页码:685 / 693
页数:9
相关论文
共 24 条
[1]   POSSIBLE ROLE FOR WATER DISSOCIATION IN THE SLOW BINDING OF PHOSPHORUS-CONTAINING TRANSITION-STATE-ANALOGUE INHIBITORS OF THERMOLYSIN [J].
BARTLETT, PA ;
MARLOWE, CK .
BIOCHEMISTRY, 1987, 26 (26) :8553-8561
[2]   EVALUATION OF INTRINSIC BINDING-ENERGY FROM A HYDROGEN-BONDING GROUP IN AN ENZYME-INHIBITOR [J].
BARTLETT, PA ;
MARLOWE, CK .
SCIENCE, 1987, 235 (4788) :569-571
[3]  
BOND MD, 1984, BIOCHEMISTRY-US, V23, P3077, DOI 10.1021/bi00308a035
[4]   CHARACTERIZATION OF THE INDIVIDUAL COLLAGENASES FROM CLOSTRIDIUM-HISTOLYTICUM [J].
BOND, MD ;
VANWART, HE .
BIOCHEMISTRY, 1984, 23 (13) :3085-3091
[5]  
BOND MD, 1984, BIOCHEMISTRY-US, V23, P3091
[6]  
BUNNING P, 1983, BIOCHEMISTRY-US, V22, P103
[7]   STUDIES ON BACILLUS-SUBTILIS NEUTRAL-PROTEASE-CATALYZED AND BACILLUS-THERMOPROTEOLYTICUS THERMOLYSIN-CATALYZED HYDROLYSIS OF DIPEPTIDE SUBSTRATES [J].
FEDER, J ;
SCHUCK, JM .
BIOCHEMISTRY, 1970, 9 (14) :2784-&
[8]   INHIBITION OF COLLAGENASE FROM CLOSTRIDIUM-HISTOLYTICUM BY PHOSPHORIC AND PHOSPHONIC AMIDES [J].
GALARDY, RE ;
GROBELNY, D .
BIOCHEMISTRY, 1983, 22 (19) :4556-4561
[9]   BINDING ENERGETICS OF PHOSPHORUS-CONTAINING INHIBITORS OF THERMOLYSIN [J].
GROBELNY, D ;
GOLI, UB ;
GALARDY, RE .
BIOCHEMISTRY, 1989, 28 (12) :4948-4951
[10]   PHOSPHONATE ANALOGS OF CARBOXYPEPTIDASE-A SUBSTRATES ARE POTENT TRANSITION-STATE ANALOG INHIBITORS [J].
HANSON, JE ;
KAPLAN, AP ;
BARTLETT, PA .
BIOCHEMISTRY, 1989, 28 (15) :6294-6305