The β-Carbonic Anhydrases from Mycobacterium tuberculosis as Drug Targets

被引:72
作者
Nishimori, Isao [2 ]
Minakuchi, Tomoko [2 ]
Maresca, Alfonso [1 ]
Carta, Fabrizio [1 ]
Scozzafava, Andrea [1 ]
Supuran, Claudiu T. [1 ]
机构
[1] Univ Florence, Lab Chim Bioinorgan, I-50019 Florence, Italy
[2] Kochi Med Sch, Dept Gastroenterol, Nanko Ku, Kochi 7838505, Japan
关键词
carbonic anhydrase; mycobacterium tuberculosis; beta-Class enzyme; sulfonamide; antituberculosis agents; YEAST SACCHAROMYCES-CEREVISIAE; PATHOGENS CANDIDA-ALBICANS; INHIBITORS; INHIBITION; HELICOBACTER-PYLORI; CRYPTOCOCCUS-NEOFORMANS; CRYSTAL-STRUCTURE; CLASS ENZYMES; CLONING; RV1284; IDENTIFICATION;
D O I
10.2174/138161210793429814
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Three beta-carbonic anhydrases (CAs, EC 4.2.1.1), encoded by the gene Rv1284 (mtCA 1) Rv3588c (mtCA 2) and Rv3273 (mtCA 3) are present in the human pathogen Mycobacterium tuberculosis. These enzymes were cloned and they showed appreciable catalytic activity for CO2 hydration, with k(cat) of 3.9 x 10(5) s(-1), and k(cat)/K-m of 3.7 x 10(7) M-1.s(-1) for mtCA 1, of 9.8 x 10(5) s(-1), and k(cat)/K-m of 9.3 x 10(7) M-1.s(-1) for mtCA 2 and k(cat) of 4.3 x 10(5) s(-1), and a k(cat)/K-m of 4.0 x 10(7) M-1.s(-1) for mtCA 3, respectively. The Rv3273 gene product is predicted to be a 764 amino acid residues polypeptide, consisting of a sulfate transporter domain (amino acids 121-414) in addition to the beta-CA mentioned above (which is encoded by residues 571-741). All these enzymes were inhibited appreciably by many sulfonamides and sulfamates, in the nanomolar - micromolar range, whereas some subnanomolar inhibitors were also reported for two of them (mtCA 1 and mtCA 3). As sulfonamides also efficiently inhibit dehydropteroate synthetase (DHPS), the contribution of mtCAs and DHPS inhibition to a possible antimycobacterial action of these drugs must be better understood. It has been however proven that mtCAs are drug-gable targets, with a real potential for developing antimycobacterial agents with a diverse mechanism of action compared to the clinically used drugs for which many strains exhibit multi-drug resistance and extensive multi-drug resistance, although for the moment no in vivo inhibition of the bacteria could be evidenced with the presently avilable drugs due to lack of penetrability through the mycolic acid cell wall of M. tuberculosis.
引用
收藏
页码:3300 / 3309
页数:10
相关论文
共 37 条
[1]   Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling [J].
Betts, JC ;
Lukey, PT ;
Robb, LC ;
McAdam, RA ;
Duncan, K .
MOLECULAR MICROBIOLOGY, 2002, 43 (03) :717-731
[2]   Carbonic anhydrase inhibitors. Characterization and inhibition studies of the most active β-carbonic anhydrase from Mycobacterium tuberculosis, Rv3588c [J].
Carta, Fabrizio ;
Maresca, Alfonso ;
Covarrubias, Adrian Suarez ;
Mowbray, Sherry L. ;
Jones, T. Alwyn ;
Supuran, Claudiu T. .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (23) :6649-6654
[3]   Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence [J].
Cole, ST ;
Brosch, R ;
Parkhill, J ;
Garnier, T ;
Churcher, C ;
Harris, D ;
Gordon, SV ;
Eiglmeier, K ;
Gas, S ;
Barry, CE ;
Tekaia, F ;
Badcock, K ;
Basham, D ;
Brown, D ;
Chillingworth, T ;
Connor, R ;
Davies, R ;
Devlin, K ;
Feltwell, T ;
Gentles, S ;
Hamlin, N ;
Holroyd, S ;
Hornby, T ;
Jagels, K ;
Krogh, A ;
McLean, J ;
Moule, S ;
Murphy, L ;
Oliver, K ;
Osborne, J ;
Quail, MA ;
Rajandream, MA ;
Rogers, J ;
Rutter, S ;
Seeger, K ;
Skelton, J ;
Squares, R ;
Squares, S ;
Sulston, JE ;
Taylor, K ;
Whitehead, S ;
Barrell, BG .
NATURE, 1998, 393 (6685) :537-+
[4]   Structural mechanics of the pH-dependent activity of β-carbonic anhydrase from Mycobacterium tuberculosis [J].
Covarrubias, AS ;
Bergfors, T ;
Jones, TA ;
Högbom, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (08) :4993-4999
[5]   Identification of a novel noncatalytic bicarbonate binding site in eubacterial β-carbonic anhydrase [J].
Cronk, JD ;
Rowlett, RS ;
Zhang, KYJ ;
Tu, CK ;
Endrizzi, JA ;
Lee, J ;
Gareiss, PC ;
Preiss, JR .
BIOCHEMISTRY, 2006, 45 (14) :4351-4361
[6]   Crystal structure of E-coli β-carbonic anhydrase, an enzyme with an unusual pH-dependent activity [J].
Cronk, JD ;
Endrizzi, JA ;
Cronk, MR ;
O'Neill, JW ;
Zhang, KYJ .
PROTEIN SCIENCE, 2001, 10 (05) :911-922
[7]   Doomsday postponed? Preventing and reversing epidemics of drug-resistant tuberculosis [J].
Dye, Christopher .
NATURE REVIEWS MICROBIOLOGY, 2009, 7 (01) :81-87
[8]   Emerging drugs for active tuberculosis [J].
Ginsberg, Ann M. .
SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE, 2008, 29 (05) :552-559
[9]   Discovery of Low Nanomolar and Subnanomolar Inhibitors of the Mycobacterial β-Carbonic Anhydrases Rv1284 and Rv3273 [J].
Guzel, Ozlen ;
Maresca, Alfonso ;
Scozzafava, Andrea ;
Salman, Aydin ;
Balaban, Alexandru T. ;
Supuran, Claudiu T. .
JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (13) :4063-4067
[10]   Carbonic anhydrase inhibitors:: Inhibition of the β-class enzymes from the fungal pathogens Candida albicans and Cryptococcus neoformans with simple anions [J].
Innocenti, Alessio ;
Muehlschlegel, Fritz A. ;
Hall, Rebecca A. ;
Steegborn, Clemens ;
Scozzafava, Andrea ;
Supuran, Claudiu T. .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (18) :5066-5070