Structural highlights
Function
MABA_MYCTU Part of the mycobacterial fatty acid elongation system FAS-II, which is involved in mycolic acid biosynthesis (PubMed:11932442). Catalyzes the NADPH-dependent reduction of beta-ketoacyl derivatives, the second step of the FAS-II elongation cycle (PubMed:9802011, PubMed:11932442, PubMed:17059223, PubMed:18155153, PubMed:19685079). May preferentially metabolize long-chain substrates (C8-C20) (PubMed:11932442). Can use CoA derivatives as substrates in vitro (PubMed:9802011, PubMed:11932442, PubMed:17059223, PubMed:18155153).[1] [2] [3] [4] [5]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The MabA protein from Mycobacterium tuberculosis is a validated drug target. Previous structural studies of this protein showed dynamic behaviour in the catalytic site and described motion between an open 'active' holo form (with NADP) and a closed 'inactive' apo form (without NADP). Here, a mutation (G139A) is reported that leads to complete protein inactivation and freezes the catalytic site into its closed form, even in the presence of the cofactor. This observation suggests a new way to develop anti-MabA drugs via protein stabilization of the 'inactive' form.
Lack of dynamics in the MabA active site kills the enzyme activity: practical consequences for drug-design studies.,Poncet-Montange G, Ducasse-Cabanot S, Quemard A, Labesse G, Cohen-Gonsaud M Acta Crystallogr D Biol Crystallogr. 2007 Aug;63(Pt 8):923-5. Epub 2007, Jul 17. PMID:17642518[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Marrakchi H, Ducasse S, Labesse G, Montrozier H, Margeat E, Emorine L, Charpentier X, Daffe M, Quemard A. MabA (FabG1), a Mycobacterium tuberculosis protein involved in the long-chain fatty acid elongation system FAS-II. Microbiology. 2002 Apr;148(Pt 4):951-60. PMID:11932442
- ↑ Silva RG, de Carvalho LP, Blanchard JS, Santos DS, Basso LA. Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein (ACP) reductase: kinetic and chemical mechanisms. Biochemistry. 2006 Oct 31;45(43):13064-73. PMID:17059223 doi:10.1021/bi0611210
- ↑ Silva RG, Rosado LA, Santos DS, Basso LA. Mycobacterium tuberculosis beta-ketoacyl-ACP reductase: alpha-secondary kinetic isotope effects and kinetic and equilibrium mechanisms of substrate binding. Arch Biochem Biophys. 2008 Mar 1;471(1):1-10. PMID:18155153 doi:10.1016/j.abb.2007.12.002
- ↑ Gurvitz A. The essential mycobacterial genes, fabG1 and fabG4, encode 3-oxoacyl-thioester reductases that are functional in yeast mitochondrial fatty acid synthase type 2. Mol Genet Genomics. 2009 Oct;282(4):407-16. Epub 2009 Aug 14. PMID:19685079 doi:http://dx.doi.org/10.1007/s00438-009-0474-2
- ↑ Banerjee A, Sugantino M, Sacchettini JC, Jacobs WR Jr. The mabA gene from the inhA operon of Mycobacterium tuberculosis encodes a 3-ketoacyl reductase that fails to confer isoniazid resistance. Microbiology. 1998 Oct;144 ( Pt 10):2697-704. PMID:9802011
- ↑ Poncet-Montange G, Ducasse-Cabanot S, Quemard A, Labesse G, Cohen-Gonsaud M. Lack of dynamics in the MabA active site kills the enzyme activity: practical consequences for drug-design studies. Acta Crystallogr D Biol Crystallogr. 2007 Aug;63(Pt 8):923-5. Epub 2007, Jul 17. PMID:17642518 doi:10.1107/S0907444907024158
