Pyridoxal 5′-phosphate enzymes as targets for therapeutic agents

被引:157
作者
Amadasi, Alessio
Bertoldi, Mariarita
Contestabile, Roberto
Bettati, Stefano
Cellini, Barbara
di Salvo, Martino Luigi
Borri-Voltattorni, Carla
Bossa, Francesco
Mozzarelli, Andrea
机构
[1] Univ Parma, Dipartmento Biochim & Biol Mol, I-43100 Parma, Italy
[2] Univ Verona, Sez Chim Biol, Dipartimento Sci Morfol Biomed, I-37100 Verona, Italy
[3] Univ Roma La Sapienza, Dipartimento Sci Biochim A Rossi Fanelli, Rome, Italy
关键词
vitamin B-6; enzyme; drug design; pyridoxal 5 '-phosphate; inhibitors; X-ray structure; functional genomics; inhibition mechanism;
D O I
10.2174/092986707780597899
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
The vitamin B-6-derived pyridoxal 5'-phosphate (PLP) is the cofactor of enzymes catalyzing a large variety of chemical reactions mainly involved in amino acid metabolism. These enzymes have been divided in five families and fold types on the, p-basis of evolutionary relationships and protein structural organization. Almost 1.5% of all genes in prokaryotes code for PLP-dependent enzymes, whereas the percentage is substantially lower in eukaryotes. Although about 4% of enzyme-catalyzed reactions catalogued by the Enzyme Commission are PLP-dependent, only a few enzymes are targets of approved drugs and about twenty are recognised as potential targets for drugs or herbicides. PLP-dependent enzymes for which there are already commercially available drugs are DOPA clecarboxylase (involved in the Parkinson disease), GABA aminotransferase (epilepsy), scrine hydroxymethyltransferase (tumors and malaria), ornithine decarboxylase (African sleeping sickness and, potentially, tumors), alanine racemase (antibacterial agents), and human cytosolic branched-chain aminotransferase (pathological states associated to the GABA/glutamate equilibrium concentrations). Within each family or metabolic pathway, the enzymes for which drugs have been already approved for clinical use are discussed first, reporting the enzyme structure, the catalytic mechanism, the mechanism of enzyme inactivation or modulation by substrate-like or transition state-like drugs, and on-going research for increasing specificity and decreasing side-effects. Then, PLP-dependent enzymes that have been recently characterized and proposed as drug targets are reported. Finally, the relevance of recent genomic analysis of PI-P-dependent enzymes for the selection of drug targets is discussed.
引用
收藏
页码:1291 / 1324
页数:34
相关论文
共 441 条
[21]   Severe visual-field constriction and side-effects of GABA-mimetic antiepileptic agents [J].
Baulac, M ;
Nordmann, JP ;
Lanoé, Y .
LANCET, 1998, 352 (9127) :546-546
[22]  
BAXTER CF, 1958, J BIOL CHEM, V233, P1135
[23]   EVOLUTION IN BIOSYNTHETIC PATHWAYS - 2 ENZYMES CATALYZING CONSECUTIVE STEPS IN METHIONINE BIOSYNTHESIS ORIGINATE FROM A COMMON ANCESTOR AND POSSESS A SIMILAR REGULATORY REGION [J].
BELFAIZA, J ;
PARSOT, C ;
MARTEL, A ;
DELATOUR, CB ;
MARGARITA, D ;
COHEN, GN ;
SAINTGIRONS, I .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1986, 83 (04) :867-871
[24]   Methionine regeneration and aminotransferases in Bacillus subtilis, Bacillus cereus, and Bacillus anthracis [J].
Berger, BJ ;
English, S ;
Chan, G ;
Knodel, MH .
JOURNAL OF BACTERIOLOGY, 2003, 185 (08) :2418-2431
[25]   Gabapentin monotherapy .1. An 8-day, double-blind, dose-controlled, multicenter study in hospitalized patients with refractory complex partial or secondarily generalized seizures [J].
Bergey, GK ;
Morris, HH ;
Rosenfeld, W ;
Blume, WT ;
Penovich, PE ;
Morrell, MJ ;
Leiderman, DB ;
Crockatt, JG ;
LaMoreaux, L ;
Garofalo, E ;
Pierce, M .
NEUROLOGY, 1997, 49 (03) :739-745
[26]   A quinonoid is an intermediate of oxidative deamination reaction catalyzed by Dopa decarboxylase [J].
Bertoldi, M ;
Cellini, B ;
Maras, B ;
Voltattorni, CB .
FEBS LETTERS, 2005, 579 (23) :5175-5180
[27]   Lysine 238 is an essential residue for α,β-elimination catalyzed by Treponema denticola cystalysin [J].
Bertoldi, M ;
Cellini, B ;
D'Aguanno, S ;
Voltattorni, CB .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (39) :37336-37343
[28]   Spectroscopic and kinetic analyses reveal the pyridoxal 5′-phosphate binding mode and the catalytic features of Treponema denticola cystalysin [J].
Bertoldi, M ;
Cellini, B ;
Clausen, T ;
Voltattorni, CB .
BIOCHEMISTRY, 2002, 41 (29) :9153-9164
[29]   Treponema denticola cystalysin exhibits significant alanine racemase activity accompanied by transamination:: mechanistic implications [J].
Bertoldi, M ;
Cellini, B ;
Paiardini, A ;
Di Salvo, M ;
Voltattorni, CB .
BIOCHEMICAL JOURNAL, 2003, 371 :473-483
[30]   Mutation of tyrosine 332 to phenylalanine converts dopa decarboxylase into a decarboxylation-dependent oxidative deaminase [J].
Bertoldi, M ;
Gonsalvi, M ;
Contestabile, R ;
Voltattorni, CB .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (39) :36357-36362