Просмотр кода страницы Английская Википедия:Beta-ketoacyl-ACP synthase III

{{Английская Википедия/Панель перехода}}
{{Short description|Enzyme}}
{{About|the specific variant of the enzyme type III|the function and the enzyme in general|Beta-ketoacyl-ACP synthase}}
{{infobox enzyme
| Name       = β-ketoacyl-(acyl-carrier-protein) synthase III
| EC_number  = 2.3.1.180
| CAS_number = 9077-10-5
| GO_code    = 00061
| image      =
| width      = 
| caption    =  
}}
{{Infobox protein family
| Symbol = ACP_syn_III
| Name = 3-Oxoacyl-[acyl-carrier-protein (ACP)] synthase III
| image = PDB 1ebl EBI.jpg
| width = 
| caption = Structure and active-site architecture of beta-ketoacyl-acyl carrier protein synthase III (FabH) from ''escherichia coli''.<ref name="pmid10673437">{{cite journal | vauthors = Davies C, Heath RJ, White SW, Rock CO | title = The 1.8 A crystal structure and active-site architecture of beta-ketoacyl-acyl carrier protein synthase III (FabH) from escherichia coli | journal = Structure | volume = 8 | issue = 2 | pages = 185–95 | year = 2000 | pmid = 10673437 | doi = 10.1016/S0969-2126(00)00094-0 | doi-access = free }}</ref>
| Pfam = PF08545
| InterPro = IPR013751
| SMART = 
| PROSITE = 
| SCOP = 
| TCDB = 
| OPM family = 
| OPM protein = 
}}

In [[enzymology]], a β-ketoacyl-[acyl-carrier-protein] synthase III ({{EC number|2.3.1.180}}) is an [[enzyme]] that [[catalysis|catalyzes]] the [[chemical reaction]]

:acetyl-CoA + malonyl-<nowiki>[</nowiki>[[acyl carrier protein]]<nowiki>]</nowiki> <math>\rightleftharpoons</math> acetoacetyl-<nowiki>[</nowiki>[[acyl carrier protein]]<nowiki>]</nowiki> + CoA + CO<sub>2</sub>

Thus, the two [[substrate (biochemistry)|substrates]] of this enzyme are [[acetyl-CoA]] and malonyl-[acyl-carrier-protein], whereas its 3 [[product (chemistry)|products]] are acetoacetyl-[acyl-carrier-protein], [[coenzyme A|CoA]], and [[carbon dioxide|CO<sub>2</sub>]]. This enzyme belongs to the family of [[transferase]]s, to be specific those [[acyltransferase]]s transferring groups other than aminoacyl groups.

This enzyme participates in [[fatty acid biosynthesis]]. β-Ketoacyl-acyl-carrier-protein synthase III is involved in the dissociated (or type II) fatty-acid biosynthesis system that occurs in plants and bacteria. The role of FabH in fatty acid synthesis has been described in ''Streptomyces glaucescens'',<ref>{{cite journal | vauthors = Han L, Lobo S, Reynolds KA | title = Characterization of β-Ketoacyl-Acyl Carrier Protein Synthase III from Streptomyces glaucescens and Its Role in Initiation of Fatty Acid Biosynthesis | journal = J. Bacteriol. | volume = 180 | issue = 17 | pages = 4481&ndash;6 | date = 1998 | doi = 10.1128/JB.180.17.4481-4486.1998 | pmid = 9721286 | pmc = 107458 }}</ref> ''[[Streptococcus pneumoniae]]'',<ref>{{cite journal | vauthors = Khandekar SS, Gentry DR, Van Aller GS, Warren P, Xiang H, Silverman C, Doyle ML, Chambers PA, Konstantinidis AK, Brandt M, Daines RA, Lonsdale JT | title = Identification, substrate specificity, and inhibition of the ''Streptococcus pneumoniae'' beta-ketoacyl-acyl carrier protein synthase III (FabH) | journal = J. Biol. Chem. | volume = 276 | issue = 32 | pages = 30024&ndash;30 | date = 2001 | pmid = 11375394 | doi = 10.1074/jbc.M101769200 | s2cid = 40184365 | doi-access = free }}</ref> and ''Streptomyces coelicolor''.<ref>{{cite journal | vauthors = Li Y, Florova G, Reynolds KA | title = Alteration of the Fatty Acid Profile of Streptomyces coelicolor by Replacement of the Initiation Enzyme 3-Ketoacyl Acyl Carrier Protein Synthase III (FabH) | journal = J. Bacteriol. | volume = 187 | issue = 11 | pages = 3795&ndash;9 | date = 2005 | pmid = 15901703 | pmc = 1112031 | doi = 10.1128/JB.187.11.3795-3799.2005 }}</ref>

== Nomenclature ==

The [[List of enzymes|systematic name]] of this enzyme class is acetyl-CoA:malonyl-[acyl-carrier-protein] C-acyltransferase. Other names in common use include:
{| 
| 
* 3-Oxoacyl:ACP synthase III 
* 3-Ketoacyl-acyl carrier protein synthase III,
* KASIII
* KAS III 
* '''FabH''' 
|
* β-Ketoacyl-acyl carrier protein synthase III
* β-Ketoacyl-ACP synthase III
* β-Ketoacyl (acyl carrier protein) synthase III 
* β-Ketoacyl-acyl-carrier-protein synthase III.  
|}

== Role in tuberculosis ==

''[[Mycobacterium tuberculosis]]'', the cause of [[tuberculosis]], evades effective immune clearance through encapsulation, especially with mycolic acids that are particularly resistant to the normal degradative processes of macrophages. Furthermore, this capsule inhibits entry of antibiotics. The enzymes involved in mycolate biosynthesis are essential for survival and pathogenesis, and thus represent excellent drug targets.

In ''M. tuberculosis'', the beta-ketoacyl-[acyl-carrier-protein] synthase III enzyme is designated mtFabH and is a crucial link between the [[fatty acid synthase]]-I and [[fatty acid synthase]]-II pathways producing [[mycolic acid]]s. FAS-I is involved in the synthesis of C<sub>16</sub> and C<sub>26</sub> fatty acids. The C<sub>16</sub> acyl-CoA product acts as a substrate for the synthesis of meromycolic acid by FAS-II, whereas the C<sub>26</sub> fatty acid constitutes the alpha branch of the final mycolic acid. MtFabH has been proposed to be the link between FAS-I and FAS-II by converting C14-CoA generated by FAS-I to C<sub>16</sub>-AcpM, which is channelled into the FAS-II cycle.<ref name="pmid17555433">{{cite journal | vauthors = Bhatt A, Molle V, Besra GS, Jacobs WR, Kremer L | title = The Mycobacterium tuberculosis FAS-II condensing enzymes: their role in mycolic acid biosynthesis, acid-fastness, pathogenesis and in future drug development | journal = Mol. Microbiol. | volume = 64 | issue = 6 | pages = 1442–54 | date = June 2007 | pmid = 17555433 | doi = 10.1111/j.1365-2958.2007.05761.x | s2cid = 32586686 | doi-access = free }}</ref> According to ''in silico'' flux balance analyses,<ref name="pmid16261191">{{cite journal | vauthors = Raman K, Rajagopalan P, Chandra N | title = Flux Balance Analysis of Mycolic Acid Pathway: Targets for Anti-Tubercular Drugs | journal = PLOS Comput. Biol. | volume = 1 | issue = 5 | pages = e46 | date = October 2005 | pmid = 16261191 | pmc = 1246807 | doi = 10.1371/journal.pcbi.0010046 | bibcode = 2005PLSCB...1...46R | doi-access = free }}</ref> mtFabH is essential but not according to transposon site hybridization analysis.<ref name="pmid12657046">{{cite journal | vauthors = Sassetti CM, Boyd DH, Rubin EJ | title = Genes required for mycobacterial growth defined by high density mutagenesis | journal = Mol. Microbiol. | volume = 48 | issue = 1 | pages = 77–84 | date = April 2003 | pmid = 12657046 | doi = 10.1046/j.1365-2958.2003.03425.x | s2cid = 21383026 | doi-access = free }}</ref> Unlike the enzymes in FAS-I, the enzymes of FAS-II, including mtFabH, and are not found in mammals, suggesting inhibitors of these enzymes are suitable choices for drug development.

== Structure and substrates ==

[[Image:mtFabH ribbons b-w active sites color.png|thumb|right|300px|'''The structure of mtFabH'''. The enzyme is a homodimer of mixed α-helices and β-sheets, or a thiolase fold. The catalytic triads of C122, H258, and N289 are shown in colour and are largely buried in hydrophobic pockets.]]
Crystal structures of FabH have been reported from ''[[Mycobacterium tuberculosis]]'',<ref name="pmid10673437" /><ref name="pmid11243824">{{PDB|1HND}}, {{PDB2|1HNH}}, {{PDB2|1HNJ}}; {{cite journal | vauthors = Qiu X, Janson CA, Smith WW, Head M, Lonsdale J, Konstantinidis AK | title = Refined structures of beta-ketoacyl-acyl carrier protein synthase III | journal = J. Mol. Biol. | volume = 307 | issue = 1 | pages = 341–56 | date = March 2001 | pmid = 11243824 | doi = 10.1006/jmbi.2000.4457 }}</ref><ref name="pmid11278743">{{PDB|1HZP}}; {{cite journal | vauthors = Scarsdale JN, Kazanina G, He X, Reynolds KA, Wright HT | title = Crystal structure of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III | journal = J. Biol. Chem. | volume = 276 | issue = 23 | pages = 20516–22 | date = June 2001 | pmid = 11278743 | doi = 10.1074/jbc.M010762200 | s2cid = 21814082 | doi-access = free }}</ref> ''[[Staphylococcus aureus]]'',<ref name="pmid15987898">{{PDB|1ZOW}}; {{cite journal | vauthors = Qiu X, Choudhry AE, Janson CA, Grooms M, Daines RA, Lonsdale JT, Khandekar SS | title = Crystal structure and substrate specificity of the β-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus | journal = Protein Sci. | volume = 14 | issue = 8 | pages = 2087–94 | date = August 2005 | pmid = 15987898 | pmc = 2279320 | doi = 10.1110/ps.051501605 }}</ref> ''[[Escherichia coli]]'',<ref name="pmid10593943">{{PDB|1HN9}}; {{cite journal | vauthors = Qiu X, Janson CA, Konstantinidis AK, Nwagwu S, Silverman C, Smith WW, Khandekar S, Lonsdale J, Abdel-Meguid SS | title = Crystal structure of beta-ketoacyl-acyl carrier protein synthase III. A key condensing enzyme in bacterial fatty acid biosynthesis | journal = J. Biol. Chem. | volume = 274 | issue = 51 | pages = 36465–71 | date = December 1999 | pmid = 10593943 | doi = 10.1074/jbc.274.51.36465 | doi-access = free }}</ref> and ''[[Thermus thermophilus]]''.<ref>{{PDB|1UB7}}Inagaki E, Kuramitsu S, Yokoyama S, Miyano M, Tahirov TH (2007) The Crystal Structure of Beta-Ketoacyl-[Acyl Carrier Protein] Synthase III (Fabh) from ''Thermus thermophilus''.</ref>

The catalytic activity and substrate specificity of mtFabH has been measured<ref name="pmid10840036">{{cite journal | vauthors = Choi KH, Kremer L, Besra GS, Rock CO | title = Identification and substrate specificity of beta -ketoacyl (acyl carrier protein) synthase III (mtFabH) from Mycobacterium tuberculosis | journal = J. Biol. Chem. | volume = 275 | issue = 36 | pages = 28201–7 | date = September 2000 | pmid = 10840036 | doi = 10.1074/jbc.M003241200| doi-access = free }}</ref> then further probed using crystallographic and directed mutagenesis methods.<ref name="pmid16040614">{{PDB|1M1M}}, {{PDB2|2AJ9}}; {{cite journal | vauthors = Brown AK, Sridharan S, Kremer L, Lindenberg S, Dover LG, Sacchettini JC, Besra GS | title = Probing the mechanism of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III mtFabH: factors influencing catalysis and substrate specificity | journal = J. Biol. Chem. | volume = 280 | issue = 37 | pages = 32539–47 | date = September 2005 | pmid = 16040614 | doi = 10.1074/jbc.M413216200 | doi-access = free }}</ref> Structures have been determined of ecFabH bound with substrates, (CoA, malonyl CoA, degraded CoA).<ref name="pmid11243824"/> Specific inhibitors developed using rational design have recently been reported.<ref name="pmid12502353">{{PDB|1MZS}}; {{cite journal | vauthors = Daines RA, Pendrak I, Sham K, Van Aller GS, Konstantinidis AK, Lonsdale JT, Janson CA, Qiu X, Brandt M, Khandekar SS, Silverman C, Head MS | title = First X-ray cocrystal structure of a bacterial FabH condensing enzyme and a small molecule inhibitor achieved using rational design and homology modeling | journal = J. Med. Chem. | volume = 46 | issue = 1 | pages = 5–8 | date = January 2003 | pmid = 12502353 | doi = 10.1021/jm025571b }}</ref><ref name="pmid15743201">{{cite journal | vauthors = Nie Z, Perretta C, Lu J, Su Y, Margosiak S, Gajiwala KS, Cortez J, Nikulin V, Yager KM, Appelt K, Chu S | title = Structure-based design, synthesis, and study of potent inhibitors of beta-ketoacyl-acyl carrier protein synthase III as potential antimicrobial agents | journal = J. Med. Chem. | volume = 48 | issue = 5 | pages = 1596–609 | date = March 2005 | pmid = 15743201 | doi = 10.1021/jm049141s }}</ref><ref name="pmid16275103">{{cite journal | vauthors = Ashek A, Cho SJ | title = A combined approach of docking and 3D QSAR study of beta-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors | journal = Bioorg. Med. Chem. | volume = 14 | issue = 5 | pages = 1474–82 | date = March 2006 | pmid = 16275103 | doi = 10.1016/j.bmc.2005.10.001 }}</ref> In 2005, the structure of a catalytically disabled mtFabH mutant with lauroyl-CoA was reported.<ref name="pmid15713483">{{PDB|1U6S}}; {{cite journal | vauthors = Musayev F, Sachdeva S, Scarsdale JN, Reynolds KA, Wright HT | title = Crystal structure of a substrate complex of Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III (FabH) with lauroyl-coenzyme A | journal = J. Mol. Biol. | volume = 346 | issue = 5 | pages = 1313–21 | date = March 2005 | pmid = 15713483 | doi = 10.1016/j.jmb.2004.12.044 }}</ref>

Native mtFabH is a homodimer with M<sub>r</sub> = 77 ± 25 kDa. Although there is substantial structural homology among all bacterial FabH enzymes determined thus far, with two channels for binding of acyl-CoA and malonyl-ACP substrates and a conserved catalytic triad (C122, H258, N289 in mtFabH), mtFabH contains residues along the acyl-CoA binding channel that preferentially select for longer-chain substrates peaking with lauroyl-CoA (C<sub>12</sub>). Inhibition strategies based on rational design could include competitive displacement of the substrates or disruption of the catalytic site. Phosphorylation of Thr<sup>45</sup>, which is located at the entrance of the substrate channel, inhibits activity, perhaps by altering accessibility of substrates.<ref name="pmid19074144">{{cite journal | vauthors = Veyron-Churlet R, Molle V, Taylor RC, Brown AK, Besra GS, Zanella-Cléon I, Fütterer K, Kremer L | title = The Mycobacterium tuberculosis β-Ketoacyl-Acyl Carrier Protein Synthase III Activity Is Inhibited by Phosphorylation on a Single Threonine Residue | journal = J. Biol. Chem. | volume = 284 | issue = 10 | pages = 6414–24 | date = March 2009 | pmid = 19074144 | pmc = 2649087 | doi = 10.1074/jbc.M806537200 | doi-access = free }}</ref>
[[Image:mtFabH Acyl-CoA specificity.gif|thumb|right|300px|'''Substrate specificity of mtFabH in relation to acyl-CoA chain length'''. The optimum length is lauroyl-CoA, C<sub>12</sub>.]]

== Inhibitors ==

At least two of the existing drugs for tuberculosis were originally derived from microbes; cerulenin from the fungus ''Cephalosporium caerulens'' and thiolactomycin (TLM) from the actinomycete ''Nocardia'' spp. Isoniazid (isonicotinic acid hydrazide), ethionamide, triclosan <nowiki>[</nowiki>5-chloro-2-(2,4-dichlorophenoxy)-phenol<nowiki>]</nowiki> and TLM are known to specifically inhibit mycolic acid biosynthesis.<ref name="pmid12164478">{{cite journal | vauthors = Schroeder EK, de Souza N, Santos DS, Blanchard JS, Basso LA | title = Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis | journal = Curr Pharm Biotechnol | volume = 3 | issue = 3 | pages = 197–225 | date = September 2002 | pmid = 12164478 | doi = 10.2174/1389201023378328 }}</ref> Derivatives of TLM and related compounds are being screened to improve efficacy.<ref name="pmid14552758">{{cite journal | vauthors = Senior SJ, Illarionov PA, Gurcha SS, Campbell IB, Schaeffer ML, Minnikin DE, Besra GS | title = Biphenyl-based analogues of thiolactomycin, active against Mycobacterium tuberculosis mtFabH fatty acid condensing enzyme | journal = Bioorg. Med. Chem. Lett. | volume = 13 | issue = 21 | pages = 3685–8 | date = November 2003 | pmid = 14552758 | doi = 10.1016/j.bmcl.2003.08.015 }}</ref><ref name="pmid14698162">{{cite journal | vauthors = Senior SJ, Illarionov PA, Gurcha SS, Campbell IB, Schaeffer ML, Minnikin DE, Besra GS | title = Acetylene-based analogues of thiolactomycin, active against Mycobacterium tuberculosis mtFabH fatty acid condensing enzyme | journal = Bioorg. Med. Chem. Lett. | volume = 14 | issue = 2 | pages = 373–6 | date = January 2004 | pmid = 14698162 | doi = 10.1016/j.bmcl.2003.10.061 }}</ref><ref name="pmid15273125">{{cite journal | vauthors = He X, Reeve AM, Desai UR, Kellogg GE, Reynolds KA | title = 1,2-Dithiole-3-Ones as Potent Inhibitors of the Bacterial 3-Ketoacyl Acyl Carrier Protein Synthase III (FabH) | journal = Antimicrob. Agents Chemother. | volume = 48 | issue = 8 | pages = 3093–102 | date = August 2004 | pmid = 15273125 | pmc = 478545 | doi = 10.1128/AAC.48.8.3093-3102.2004 }}</ref><ref name="pmid19440303">{{cite journal | vauthors = Al-Balas Q, Anthony NG, Al-Jaidi B, Alnimr A, Abbott G, Brown AK, Taylor RC, Besra GS, McHugh TD, Gillespie SH, Johnston BF, Mackay SP, Coxon GD | title = Identification of 2-Aminothiazole-4-Carboxylate Derivatives Active against Mycobacterium tuberculosis H37Rv and the β-Ketoacyl-ACP Synthase mtFabH | journal = PLOS ONE | volume = 4 | issue = 5 | pages = e5617 | year = 2009 | pmid = 19440303 | pmc = 2680598 | doi = 10.1371/journal.pone.0005617 | editor1-last = Todd | bibcode = 2009PLoSO...4.5617A | editor1-first = Matthew H. | doi-access = free }}</ref>

While much has been learned from these structural studies and rational design is an excellent approach to develop novel inhibitors, alternative approaches such as bio-prospecting may reveal unexpected compounds such as an allosteric inhibitor discovered by Daines ''et al.'' This could be especially important given that phosphorylation of mycolate synthesis enzymes is suggested to be critical to regulation and kinase domains are known to have multiple control mechanisms remote from ligand binding and active sites.<ref name="pmid19074144"/>

Following the discovery that phomallenic acids isolated from a leaf litter fungus identified as ''Phoma'' sp. are inhibitors of the FabH/FabF.<ref name="pmid16436705">{{cite journal | vauthors = Young K, Jayasuriya H, Ondeyka JG, Herath K, Zhang C, Kodali S, Galgoci A, Painter R, Brown-Driver V, Yamamoto R, Silver LL, Zheng Y, Ventura JI, Sigmund J, Ha S, Basilio A, Vicente F, Tormo JR, Pelaez F, Youngman P, Cully D, Barrett JF, Schmatz D, Singh SB, Wang J | title = Discovery of FabH/FabF Inhibitors from Natural Products | journal = Antimicrob. Agents Chemother. | volume = 50 | issue = 2 | pages = 519–26 | date = February 2006 | pmid = 16436705 | pmc = 1366929 | doi = 10.1128/AAC.50.2.519-526.2006 }}</ref><ref name="pmid16562839">{{cite journal | vauthors = Ondeyka JG, Zink DL, Young K, Painter R, Kodali S, Galgoci A, Collado J, Tormo JR, Basilio A, Vicente F, Wang J, Singh SB | title = Discovery of bacterial fatty acid synthase inhibitors from a Phoma species as antimicrobial agents using a new antisense-based strategy | journal = J. Nat. Prod. | volume = 69 | issue = 3 | pages = 377–80 | date = March 2006 | pmid = 16562839 | doi = 10.1021/np050416w }}</ref> Wang ''et al.'' recently reported their discovery from the soil bacterium ''[[Streptomyces platensis]]'' of a novel natural inhibitor of FabH with ''in vivo'' activity called platencin.<ref name="pmid17456595">{{cite journal | vauthors = Wang J, Kodali S, Lee SH, Galgoci A, Painter R, Dorso K, Racine F, Motyl M, Hernandez L, Tinney E, Colletti SL, Herath K, Cummings R, Salazar O, González I, Basilio A, Vicente F, Genilloud O, Pelaez F, Jayasuriya H, Young K, Cully DF, Singh SB | title = Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 18 | pages = 7612–6 | date = May 2007 | pmid = 17456595 | pmc = 1863502 | doi = 10.1073/pnas.0700746104 | bibcode = 2007PNAS..104.7612W | doi-access = free }}</ref> These were found by screening 250,000 extracts of soil bacteria and fungi, demonstrating the viability of bio-prospecting. While a potentially useful antibiotic in its own right, it has now been shown that [[platensimycin]] is not specifically active on mtFabH.<ref name="pmid19609444">{{cite journal | vauthors = Brown AK, Taylor RC, Bhatt A, Fütterer K, Besra GS | title = Platensimycin Activity against Mycobacterial β-Ketoacyl-ACP Synthases | journal = PLOS ONE | volume = 4 | issue = 7 | pages = e6306 | year = 2009 | pmid = 19609444 | pmc = 2707616 | doi = 10.1371/journal.pone.0006306 | editor1-last = Ahmed | bibcode = 2009PLoSO...4.6306B | editor1-first = Niyaz | doi-access = free }}</ref>

It is speculated that novel inhibitors will most likely be small molecules of relatively low polarity, considering that the catalytic sites of the mtFabH homodimer are hidden in relatively hydrophobic pockets and the need to traverse capsules of established bacilli. This is supported by the poor water solubility of an inhibitor to ecFabH. It is also hoped that, by being small molecules, their synthesis or biosynthesis will be simple and cheap, thereby enhancing affordability of subsequent drugs to developing countries. Techniques for screening efficacy of inhibitors are available.<ref name="pmid11427584">{{cite journal | vauthors = Viader-Salvadó JM, Garza-González E, Valdez-Leal R, del Bosque-Moncayo MA, Tijerina-Menchaca R, Guerrero-Olazarán M | title = Mycolic Acid Index Susceptibility Method for Mycobacterium tuberculosis | journal = J. Clin. Microbiol. | volume = 39 | issue = 7 | pages = 2642–5 | date = July 2001 | pmid = 11427584 | pmc = 88200 | doi = 10.1128/JCM.39.7.2642-2645.2001 }}</ref><ref name="pmid10860506">{{cite journal | vauthors = He X, Mueller JP, Reynolds KA | title = Development of a scintillation proximity assay for beta-ketoacyl-acyl carrier protein synthase III | journal = Anal. Biochem. | volume = 282 | issue = 1 | pages = 107–14 | date = June 2000 | pmid = 10860506 | doi = 10.1006/abio.2000.4594 }}</ref>

== Therapeutic potential ==

In 2005, [[tuberculosis]] caused approximately 1.6 million deaths worldwide, 8.8 million people became sick, with 90% of these cases in developing countries, and an estimated one-third of the world's population has latent TB.<ref name="pmid12742798">{{cite journal | vauthors = Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C | title = The growing burden of tuberculosis: global trends and interactions with the HIV epidemic | journal = Arch. Intern. Med. | volume = 163 | issue = 9 | pages = 1009–21 | date = May 2003 | pmid = 12742798 | doi = 10.1001/archinte.163.9.1009 | doi-access = free | url = https://researchonline.lshtm.ac.uk/id/eprint/17507/1/The%20Growing%20Burden%20of%20Tuberculosis.pdf }}</ref><ref name="urlWHO">{{cite web| url =https://www.who.int/tb/publications/global_report/2007/download_centre/en/index.html| title =Global Tuberculosis Control 2007| date =2007| publisher =World Health Organization| archiveurl =https://web.archive.org/web/20100202185311/http://www.who.int/tb/publications/global_report/2007/download_centre/en/index.html| archivedate =2010-02-02| accessdate =2010-01-02| url-status =dead}}</ref> Despite the availability of the BCG vaccine and multiple antibiotics, until 2005 TB resurged due to multidrug resistance, exacerbated by incubation in immune-compromised AIDS victims, drug treatment non-compliance, and ongoing systemic deficiencies of healthcare in developing countries. Mortality and infection rates appear to have peaked, but TB remains a serious global problem. New effective drugs are needed to combat this disease. Inhibitors against mtFabH, or against other enzymes of the FAS-II pathway, may have broader utility, such as the treatment of multidrug-resistant ''[[Staphylococcus aureus]]'', and ''[[Plasmodium falciparum]]'', the causative agent of another serious refractory problem, [[malaria]].

Given the predominance of TB in poor countries, the commercial incentive to develop new drugs has been hampered, along with complacency and reliance on old, well-established, "first-line" drugs such as Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol. The price point is already very low: US$16–35 will buy a full six-month drug course<ref name="urlTB Alliance — An Outdated Treatment">{{cite web| url =http://www.tballiance.org/why/outdated.php| title =TB Alliance — An Outdated Treatment| publisher =Global Alliance for TB Drug Development| archiveurl =https://web.archive.org/web/20100113165524/http://www.tballiance.org/why/outdated.php| archivedate =2010-01-13| accessdate =2010-01-02| url-status =dead}}</ref> Nevertheless, new drugs are in clinical trials.<ref name="pmid17988169">{{cite journal | vauthors = Casenghi M, Cole ST, Nathan CF | title = New Approaches to Filling the Gap in Tuberculosis Drug Discovery | journal = PLOS Med. | volume = 4 | issue = 11 | pages = e293 | date = November 2007 | pmid = 17988169 | pmc = 2062479 | doi = 10.1371/journal.pmed.0040293 | doi-access = free }}</ref><ref name="urlTB Alliance — TB Drug Portfolio">{{cite web| url =http://www.tballiance.org/new/portfolio.php| title =TB Alliance — TB Drug Portfolio| publisher =Global Alliance for TB Drug Development| archiveurl =https://web.archive.org/web/20100113155341/http://www.tballiance.org/new/portfolio.php| archivedate =2010-01-13| accessdate =2010-01-02| url-status =dead}}</ref>

According to the Global Alliance for TB Drug Development, sales of first-line TB drugs are projected to be approximately US$315 million per year, and US$54 million for second-line treatments, yet the global economic toll of TB is at least $12 billion each year.<ref name="urlNew Study Reveals Limitations of a Complex and Challenging Global Tuberculosis Drug Marketplace - TB Alliance Newscenter">{{cite web | url = http://www.tballiance.org/newscenter/view-brief.php?id=683 | title = New Study Reveals Limitations of a Complex and Challenging Global Tuberculosis Drug Marketplace | author = | authorlink = | date = 2007-05-14 | format = | work = TB Alliance Newscenter: News Release | publisher = Global Alliance for TB Drug Development | pages = | quote = | accessdate = 2010-01-02}}</ref><ref name="url_TBA_Economics_Report">{{cite web | url = http://www.tballiance.org/downloads/publications/TBA_Economics_Report.pdf | title = The Economics of TB Drug Development | author = | authorlink = | date = 2001 | format = | website = | publisher = Global Alliance for TB Drug Development | pages = | quote = | accessdate = 2010-01-02 }}</ref>

== References ==
{{reflist|colwidth=30em}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Tsay JT, Oh W, Larson TJ, Jackowski S, Rock CO | title = Isolation and characterization of the beta-ketoacyl-acyl carrier protein synthase III gene (fabH) from Escherichia coli K-12 | journal = J. Biol. Chem. | volume = 267 | issue = 10 | pages = 6807&ndash;14 | date = 1992 | doi = 10.1016/S0021-9258(19)50498-7 | pmid = 1551888 | doi-access = free }}
{{refend}}
* {{PDBe-KB2|P9WNG3|Mycobacterium tuberculosis 3-oxoacyl-[acyl-carrier-protein] synthase 3}}

{{Acyltransferases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

[[Category:EC 2.3.1]]
[[Category:Enzymes of known structure]]
{{Навигационная таблица/Портал/Английская Википедия}}
[[Категория:Английская Википедия]]
[[Категория:Википедия]]
[[Категория:Статья из Википедии]]
[[Категория:Статья из Английской Википедии]]