10018-94-7Relevant academic research and scientific papers
Inhibition of Mycobacterium tuberculosis InhA: Design, synthesis and evaluation of new di-triclosan derivatives
Alderwick, Luke J.,Armstrong, Tom,Lamont, Malcolm,Lanne, Alice,Thomas, Neil R.
supporting information, (2020/09/18)
Multi-drug resistant tuberculosis (MDR-TB) represents a growing problem for global healthcare systems. In addition to 1.3 million deaths in 2018, the World Health Organisation reported 484,000 new cases of MDR-TB. Isoniazid is a key anti-TB drug that inhibits InhA, a crucial enzyme in the cell wall biosynthesis pathway and identical in Mycobacterium tuberculosis and M. bovis. Isoniazid is a pro-drug which requires activation by the enzyme KatG, mutations in KatG prevent activation and confer INH-resistance. ‘Direct inhibitors’ of InhA are attractive as they would circumvent the main clinically observed resistance mechanisms. A library of new 1,5-triazoles, designed to mimic the structures of both triclosan molecules uniquely bound to InhA have been synthesised. The inhibitory activity of these compounds was evaluated using isolated enzyme assays with 2 (5-chloro-2-(4-(5-(((4-(4-chloro-2-hydroxyphenoxy)benzyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenoxy)phenol) exhibiting an IC50 of 5.6 μM. Whole-cell evaluation was also performed, with 11 (5-chloro-2-(4-(5-(((4-(cyclopropylmethoxy)benzyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenoxy)phenol) showing the greatest potency, with an MIC99 of 12.9 μM against M. bovis.
A KAS-III Heterodimer in Lipstatin Biosynthesis Nondecarboxylatively Condenses C8 and C14 Fatty Acyl-CoA Substrates by a Variable Mechanism during the Establishment of a C22 Aliphatic Skeleton
Zhang, Daozhong,Zhang, Fang,Liu, Wen
supporting information, p. 3993 - 4001 (2019/03/12)
β-Ketoacyl-acyl carrier protein synthase-III (KAS-III) and its homologues are thiolase-fold proteins that typically behave as homodimers functioning in diverse thioester-based reactions for C-C, C-O, or C-N bond formation. Here, we report an exception obs
Identification of middle chain fatty Acyl-CoA Ligase responsible for the biosynthesis of 2-alkylmalonyl-CoAs for Polyketide extender unit
Miyazawa, Takeshi,Takahashi, Shunji,Kawata, Akihiro,Panthee, Suresh,Hayashi, Teruo,Shimizu, Takeshi,Nogawa, Toshihiko,Osada, Hiroyuki
, p. 26994 - 27011 (2015/11/17)
Background: Fatty acyl-CoA ligases involved in polyketide biosynthesis remain uncharacterized. Results: RevS classified in fatty acyl-AMP ligase clade was the middle chain fatty acyl-CoA ligase. Conclusion: RevS was responsible for 2-alkylmalonyl-CoA bios
Multiplexing of combinatorial chemistry in antimycin biosynthesis: Expansion of molecular diversity and utility
Yan, Yan,Chen, Jing,Zhang, Lihan,Zheng, Qingfei,Han, Ying,Zhang, Hua,Zhang, Daozhong,Awakawa, Takayoshi,Abe, Ikuro,Liu, Wen
supporting information, p. 12308 - 12312 (2013/12/04)
Diversity-oriented biosynthesis of a library of antimycin-like compounds (380 altogether) was accomplished by using multiplex combinatorial biosynthesis. The core strategy depends on the use of combinatorial chemistry at different biosynthetic stages. This approach is applicable for the diversification of polyketides, nonribosomal peptides, and the hybrids that share a similar biosynthetic logic. Copyright
Enzymatic synthesis of dilactone scaffold of antimycins
Sandy, Moriah,Rui, Zhe,Gallagher, Joe,Zhang, Wenjun
, p. 1956 - 1961 (2013/02/25)
Antimycins are a family of natural products possessing outstanding biological activities and unique structures, which have intrigued chemists for over a half century. The antimycin structural skeleton is built on a nine-membered dilactone ring containing one alkyl, one acyloxy, two methyl moieties, and an amide linkage connecting to a 3-formamidosalicylic acid. Although a biosynthetic gene cluster for antimycins was recently identified, the enzymatic logic that governs the synthesis of antimycins has not yet been revealed. In this work, the biosynthetic pathway for antimycins was dissected by both genetic and enzymatic studies for the first time. A minimum set of enzymes needed for generation of the antimycin dilactone scaffold were identified, featuring a hybrid nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) assembly line containing both cis- and trans-acting components. Several antimycin analogues were further produced using in vitro enzymatic total synthesis based on the substrate promiscuity of this NRPS-PKS machinery.
Inactivation of thiolase by 2-alkynoyl-CoA via its intrinsic isomerase activity
Wu, Long,Zeng, Jia,Deng, Guisheng,Guo, Fei,Li, Nan,Liu, Xiaojun,Chu, Xiusheng,Li, Ding
, p. 3877 - 3880 (2008/02/11)
Selective inactivation of cytosolic thiolase by 2-alkynoyl-CoA via its intrinsic isomerase activity was studied, which provides an example for rationally developing mechanism-based inhibitors based on a side activity of the enzyme, and may become a supplemental method for better treatment of cardiovascular disease and cancer.
Studies on the Metabolism of Unsaturated Fatty Acids. V. Isomerization of Thiol Esters of cis-2-Alkenoic Acids during Their Preparation and Alkaline Hydrolysis
Mizugaki, Michinao,Ito, Yoko,Hoshino, Toshiaki,Shiraishi, Takayuki,Yamanaka, Hiroshi
, p. 206 - 213 (2007/10/02)
N-Acetylcysteamine and coenzyme A esters of cis-2-alkenoic acids have been found to undergo isomerization to the corresponding trans-isomers during their preparation by the mixed anhydride method and also during their alkaline hydrolysis.The isomerization might proceed by interaction of the free thiol group and the cis-double bond of 2-alkenoic thiol esters.The use of pyridine as a base and three or more equivalents of the mixed anhydride to the thiol compound prevented the formation of the trans-isomer.Addition of hydrogen peroxide during alkaline hydrolisys also prevented the isomerization completely.
