Enoyl-Acyl Carrier Protein Reductase (InhA): A REMARKABLE TARGET TO EXTERMINATE TUBERCULOSIS

2020 ◽  
Vol 18 ◽  
Author(s):  
Surabhi Jain ◽  
Smriti Sharma ◽  
Dhrubo Jyoti Sen ◽  
Saurabh S Pandya
Keyword(s):  
Target Gene ◽  
Acyl Carrier Protein ◽  
Molar Concentration ◽  
Carrier Protein ◽  
Important Target ◽  
Mutant Strains ◽  
Cause Of Failure ◽  
Direct Inhibitors ◽  
Fas Ii

: Tuberculosis, epidemic that needs new molecules with high potency and minimum side effects. In same respect, this review emphases on important target enoyl-acyl carrier protein reductase or INHA crucial in completion of FAS II cycle. INHA retain its fame since inception of drug Isoniazid as inhibitors have long residence time hence good activity. One of the cause of failure of conventional drugs is resistance towards activating or target gene. Here, we propose direct inhibitors that doesn’t need prior activation by Kat G. Some of the categories are aryl amide, Piperazine, Thiadiazole, Benzamide etc. that are specifically active against INHA along with their Structure activity relationship. Many of them are efficient in micro molar concentration whereas Pyrazole carboxamide are active in nano molar concentration and derivative of 4-hydroxy pyridones was effective in vivo. Natural products are also in way to combat tuberculosis. Furthermore, from available proteins of wild and mutant strains new leads can be designed sucessfully by utilizing information of cocrystallized ligand.

scholarly journals In Vitro Inhibition of the Mycobacterium tuberculosis β-Ketoacyl-Acyl Carrier Protein Reductase MabA by Isoniazid

2004 ◽  
Vol 48 (1) ◽  
pp. 242-249 ◽  
Author(s):  
Stéphanie Ducasse-Cabanot ◽  
Martin Cohen-Gonsaud ◽  
Hedia Marrakchi ◽  
Michel Nguyen ◽  
Didier Zerbib ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Biosynthesis ◽  
Dynamic Equilibrium ◽  
Acyl Carrier Protein ◽  
Multidrug Resistant ◽  
Carrier Protein ◽  
Ligand Complex ◽  
Fas Ii

ABSTRACT The first-line specific antituberculous drug isoniazid inhibits the fatty acid elongation system (FAS) FAS-II involved in the biosynthesis of mycolic acids, which are major lipids of the mycobacterial envelope. The MabA protein that catalyzes the second step of the FAS-II elongation cycle is structurally and functionally related to the in vivo target of isoniazid, InhA, an NADH-dependent enoyl-acyl carrier protein reductase. The present work shows that the NADPH-dependent β-ketoacyl reduction activity of MabA is efficiently inhibited by isoniazid in vitro by a mechanism similar to that by which isoniazid inhibits InhA activity. It involves the formation of a covalent adduct between MnIII-activated isoniazid and the MabA cofactor. Liquid chromatography-mass spectrometry analyses revealed that the isonicotinoyl-NADP adduct has multiple chemical forms in dynamic equilibrium. Both kinetic experiments with isolated forms and purification of the enzyme-ligand complex strongly suggested that the molecules active against MabA activity are the oxidized derivative and a major cyclic form. Spectrofluorimetry showed that the adduct binds to the MabA active site. Modeling of the MabA-adduct complex predicted an interaction between the isonicotinoyl moiety of the inhibitor and Tyr185. This hypothesis was supported by the fact that a higher 50% inhibitory concentration of the adduct was measured for MabA Y185L than for the wild-type enzyme, while both proteins presented similar affinities for NADP+. The crystal structure of MabA Y185L that was solved showed that the substitution of Tyr185 induced no significant conformational change. The description of the first inhibitor of the β-ketoacyl reduction step of fatty acid biosynthesis should help in the design of new antituberculous drugs efficient against multidrug-resistant tubercle bacilli.

scholarly journals Antimycobacterial action of thiolactomycin: an inhibitor of fatty acid and mycolic acid synthesis.

1996 ◽  
Vol 40 (12) ◽  
pp. 2813-2819 ◽  
Author(s):  
R A Slayden ◽  
R E Lee ◽  
J W Armour ◽  
A M Cooper ◽  
I M Orme ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Acyl Carrier Protein ◽  
Mycolic Acid ◽  
Carrier Protein ◽  
Type I ◽  
Dependent Manner ◽  
Fas Ii

Thiolactomycin (TLM) possesses in vivo antimycobacterial activity against the saprophytic strain Mycobacterium smegmatis mc2155 and the virulent strain M. tuberculosis Erdman, resulting in complete inhibition of growth on solid media at 75 and 25 micrograms/ml, respectively. Use of an in vitro murine macrophage model also demonstrated the killing of viable intracellular M. tuberculosis in a dose-dependent manner. Through the use of in vivo [1,2-14C]acetate labeling of M. smegmatis, TLM was shown to inhibit the synthesis of both fatty acids and mycolic acids. However, synthesis of the shorter-chain alpha'-mycolates of M. smegmatis was not inhibited by TLM, whereas synthesis of the characteristic longer-chain alpha-mycolates and epoxymycolates was almost completely inhibited at 75 micrograms/ml. The use of M. smegmatis cell extracts demonstrated that TLM specifically inhibited the mycobacterial acyl carrier protein-dependent type II fatty acid synthase (FAS-II) but not the multifunctional type I fatty acid synthase (FAS-I). In addition, selective inhibition of long-chain mycolate synthesis by TLM was demonstrated in a dose-response manner in purified, cell wall-containing extracts of M. smegmatis cells. The in vivo and in vitro data and knowledge of the mechanism of TLM resistance in Escherichia coli suggest that two distinct TLM targets exist in mycobacteria, the beta-ketoacyl-acyl carrier protein synthases involved in FAS-II and the elongation steps leading to the synthesis of the alpha-mycolates and oxygenated mycolates. The efficacy of TLM against M. smegmatis and M. tuberculosis provides the prospects of identifying fatty acid and mycolic acid biosynthetic genes and revealing a novel range of chemotherapeutic agents directed against M. tuberculosis.

scholarly journals The Burkholderia pseudomallei Enoyl-Acyl Carrier Protein Reductase FabI1 Is Essential forIn VivoGrowth and Is the Target of a Novel Chemotherapeutic with Efficacy

2013 ◽  
Vol 58 (2) ◽  
pp. 931-935 ◽  
Author(s):  
Jason E. Cummings ◽  
Luke C. Kingry ◽  
Drew A. Rholl ◽  
Herbert P. Schweizer ◽  
Peter J. Tonge ◽  
...  
Keyword(s):  
Burkholderia Pseudomallei ◽  
Fatty Acid Biosynthesis ◽  
Acyl Carrier Protein ◽  
Specific Inhibitor ◽  
Carrier Protein ◽  
Wild Type ◽  
Content Type ◽  
Fatty Acid Biosynthesis Pathway ◽  
Enoyl Acp Reductase

ABSTRACTThe bacterial fatty acid biosynthesis pathway is a validated target for the development of novel chemotherapeutics. However, sinceBurkholderia pseudomalleicarries genes that encode both FabI and FabV enoyl-acyl carrier protein (ACP) reductase homologues, the enoyl-ACP reductase that is essential forin vivogrowth needs to be defined so that the correct drug target can be chosen for development. Accordingly, ΔfabI1, ΔfabI2, and ΔfabVknockout strains were constructed and tested in a mouse model of infection. Mice infected with a ΔfabI1strain did not show signs of morbidity, mortality, or dissemination after 30 days of infection compared to the wild-type and ΔfabI2and ΔfabVmutant strains that had times to mortality of 60 to 84 h. Although signs of morbidity and mortality of ΔfabI2and ΔfabVstrains were not significantly different from those of the wild-type strain, a slight delay was observed. A FabI1-specific inhibitor was used to confirm that inhibition of FabI1 results in reduced bacterial burden and efficacy in an acuteB. pseudomalleimurine model of infection. This work establishes that FabI1 is required for growth ofBurkholderia pseudomalleiin vivoand is a potential molecular target for drug development.

Design, Synthesis, and Evaluation of New Thiadiazole-Based Direct Inhibitors of Enoyl Acyl Carrier Protein Reductase (InhA) for the Treatment of Tuberculosis

2014 ◽  
Vol 58 (2) ◽  
pp. 613-624 ◽  
Author(s):  
Roman Šink ◽  
Izidor Sosič ◽  
Matej Živec ◽  
Raquel Fernandez-Menendez ◽  
Samo Turk ◽  
...  
Keyword(s):  
Acyl Carrier Protein ◽  
Carrier Protein ◽  
Design Synthesis ◽  
Direct Inhibitors

scholarly journals Rapid in Vivo Acylation of Acyl Carrier Protein with Exogenous Fatty Acids in Spirodela oligorrhiza

1989 ◽  
Vol 89 (2) ◽  
pp. 707-711 ◽  
Author(s):  
Autar K. Mattoo ◽  
Franklin E. Callahan ◽  
Roshni A. Mehta ◽  
John B. Ohlrogge
Keyword(s):  
Fatty Acids ◽  
Acyl Carrier Protein ◽  
Carrier Protein ◽  
Spirodela Oligorrhiza

scholarly journals Characterization of a Novel Acyl Carrier Protein, RkpF, Encoded by an Operon Involved in Capsular Polysaccharide Biosynthesis in Sinorhizobium meliloti

1998 ◽  
Vol 180 (18) ◽  
pp. 4950-4954 ◽  
Author(s):  
Guido Epple ◽  
Koen M. G. M. van der Drift ◽  
Jane E. Thomas-Oates ◽  
Otto Geiger
Keyword(s):  
Sinorhizobium Meliloti ◽  
Capsular Polysaccharide ◽  
Acyl Carrier Protein ◽  
Polyacrylamide Gel Electrophoresis ◽  
Protein Product ◽  
Spectrometric Analysis ◽  
Carrier Protein ◽  
Plant Host

ABSTRACT Rhizobial capsular polysaccharides (RKPs) play an important role in the development of a nitrogen-fixing symbiosis with the plant host and in Sinorhizobium meliloti AK631 functionalrkpABCDEF genes are required for the production of RKPs. After cloning the rkpF gene, we overexpressed and purified the derived protein product (RkpF) in Escherichia coli. Like acyl carrier protein (ACP), the RkpF protein can be labeled in vivo with radioactive β-alanine added to the growth medium. If homogeneous RkpF protein is incubated with radiolabeled coenzyme A in the presence of purified holo-ACP synthase from E. coli, an in vitro transfer of 4′-phosphopantetheine to the RkpF protein can be observed. The conversion from apo-RkpF protein to holo-RkpF protein seems to go along with a major conformational change of the protein structure, because the holo-RkpF protein runs significantly faster on native polyacrylamide gel electrophoresis than the apo-RkpF protein. Electrospray mass spectrometric analysis reveals a mass of 9,585 for the apo-RkpF protein and a mass of 9,927 for the holo-RkpF protein. Our data show that RkpF is a novel ACP.

scholarly journals Acyl Carrier Protein is essential for MukBEF action in Escherichia coli chromosome organization-segregation

2021 ◽  
Author(s):  
Josh Prince ◽  
Jani Bolla ◽  
Gemma Fisher ◽  
Jarno Makela ◽  
Majorie Fournier ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Acyl Carrier Protein ◽  
Coiled Coil ◽  
Acid Synthesis ◽  
Chromosome Organization ◽  
Carrier Protein ◽  
Accessory Proteins ◽  
Structural Maintenance Of Chromosomes ◽  
Smc Proteins

Abstract Structural Maintenance of Chromosomes (SMC) complexes contribute ubiquitously to chromosome organization-segregation. SMC proteins have a conserved architecture, with a dimerization hinge and an ATPase head domain separated by a long antiparallel intramolecular coiled-coil. Dimeric SMC proteins interact with essential accessory proteins, kleisins that bridge the two subunits of an SMC dimer, and HAWK/KITE accessory proteins that interact with kleisins. The ATPase activity of the Escherichia coli SMC protein, MukB, is essential for in vivo function and is regulated by interactions with its dimeric kleisin, MukF, and KITE, MukE. Here we demonstrate that, in addition, MukB interacts with Acyl Carrier Protein (AcpP) that has essential functions in fatty acid synthesis. We characterize the AcpP interaction site at the joint of the MukB coiled-coil and show that the interaction is essential for MukB ATPase and for MukBEF function in vivo. Therefore, AcpP is an essential co-factor for MukBEF action in chromosome organization-segregation.

scholarly journals Antibacterial Activity of N-Pentylpantothenamide Is Due to Inhibition of Coenzyme A Synthesis

2010 ◽  
Vol 54 (3) ◽  
pp. 1374-1377 ◽  
Author(s):  
Jacob Thomas ◽  
John E. Cronan
Keyword(s):  
Antibacterial Activity ◽  
Growth Inhibition ◽  
Coenzyme A ◽  
Acyl Carrier Protein ◽  
Carrier Protein ◽  
Prosthetic Group ◽  
Protein Moiety

ABSTRACT Growth inhibition by the pantothenate analog N-pentylpantothenamide (N5-Pan) has been attributed to the accumulation of acyl carrier protein carrying a prosthetic group modified by incorporation of N5-Pan. This was attributed to an inability of the AcpH acyl carrier protein phosphodiesterase to cleave the N5-Pan-modified prosthetic group from the protein moiety. We report that AcpH readily removes the N5-Pan-modified prosthetic group both in vivo and in vitro and show that N5-Pan blocks coenzyme A synthesis.

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