Acetohydroxyacid synthase and its role in the biosynthetic pathway for branched-chain amino acids

McCourt, Jennifer A.; Duggleby, Ronald G.

doi:10.1007/s00726-005-0297-3

Cited by 198 publications

(172 citation statements)

References 242 publications

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“…This conformation of BAntx AHAS is similar to that observed in the case of the A. thaliana-CE complex [1]. There are three hydrogen bonds between BAntx AHAS and CE.…”

Section: Binding Modes Of the Ligandssupporting

confidence: 83%

“…The other BAntx AHAS amino acids likely to be involved in hydrophobic and van der Waals interactions are Gly45, Ala47, Leu49, Phe130, and Lys180. Some of these residues are equivalent in A. thaliana; Phe130 is Phe206, Gln131 is Gln207, and Lys180 is Lys256 [1]. Despite major similarities between CE and SMM, the absence of the methoxy substituent on the pyrimidine ring results in a low binding affinity for SMM (Table 2).…”

Section: Binding Modes Of the Ligandsmentioning

confidence: 99%

“…This makes the enzymes of the BCAA biosynthetic pathway potential targets for herbicides, fungicides, and antimicrobial compounds. The first common enzyme in the BCAA biosynthetic pathway is FAD-and thiamin-dependent acetohydroxyacid synthase (AHAS, EC 2.2.1.6) [1]. Sulfonylureas and imidazolinones, the most popular herbicidal AHAS inhibitors currently on the market for broad-spectrum weed control in major crops, are highly selective, potent, and nontoxic to animals [2,3].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibitors of Bacillus anthracis acetohydroxyacid synthase

Kalme¹,

Pham²,

Gedi³

et al. 2008

Enzyme and Microbial Technology

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“…This conformation of BAntx AHAS is similar to that observed in the case of the A. thaliana-CE complex [1]. There are three hydrogen bonds between BAntx AHAS and CE.…”

Section: Binding Modes Of the Ligandssupporting

confidence: 83%

Section: Binding Modes Of the Ligandsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibitors of Bacillus anthracis acetohydroxyacid synthase

Kalme¹,

Pham²,

Gedi³

et al. 2008

Enzyme and Microbial Technology

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“…127 O primeiro relato envolvendo esta enzima como alvo no Mycobacterium tuberculosis é de 1998, com o herbicida inibidor de AHAS sulfometuron metil. 128 No entanto, somente após a determinação da estrutura cristalográfica da enzima foi possível o planejamento de protótipos baseados na estrutura do receptor.…”

Section: Ahasunclassified

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

2017

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POTENTIAL MOLECULAR TARGETS FOR ANTITUBERCULOSIS DRUG DISCOVERY. Tuberculosis (TB) is an infectious disease caused by mycobacteria from the Mycobacterium genus, mainly by Mycobacterium tuberculosis (MTB). The World HealthOrganization (WHO) aims to reduce the number of TB cases worldwide in the coming years. Nevertheless, the increasing number of multidrug-resistant (MDR-TB) and extensive-drug resistance (XDR-TB) strains, and the ineffectiveness of the current treatment in latent tuberculosis are challenges to be overcome. In this review, we will demonstrate the recent advances in the tuberculosis drug discovery, focusing the research of new molecular targets in the Mycobacterium tuberculosis. Among the promising targets described herein, we highlight those, which act in different pathways in the mycobacteria, such as energy metabolism, cell wall biosynthesis, DNA synthesis, iron metabolism and transport through membranes. Furthermore, bioactive compounds discovered using phenotypic assays screening and validated through genetic approaches are also presented.Keywords: medicinal chemistry; tuberculosis; Mycobacterium tuberculosis; molecular targets; new drugs. INTRODUÇÃOA tuberculose (TB) é uma doença infecciosa causada por micobactérias do complexo Mycobacterium, no entanto, a espécie responsável pelo maior número de casos de morbidade e mortalidade é o Mycobacterium tuberculosis (MTB). 1 Ocupando o ranking mundial como a principal causa de mortes causadas por doenças infecciosas, nos últimos anos a tuberculose ultrapassou, em número de casos, a infecção causada pelo vírus da imunodeficiência humana (HIV). 2,3 O último levantamento realizado em 2015 pela Organização Mundial da Saúde (OMS) apontou 9.6 milhões de novos casos no mundo e 1.5 milhões de mortes causadas pela doença. 3 Somado a esses dados, o surgimento e aumento de cepas de M. tuberculosis multirresistente aos fármacos (MDR-TB) e extensivamente resistente aos fármacos (XDR-TB) vêm alarmando as autoridades de todo o mundo. Essas formas de tuberculose apresentam baixas taxas de cura e maiores taxas de mortalidade devido às dificuldades de tratamento. 4 Além disso, já foram relatados na clínica casos de tuberculose totalmente resistente aos fármacos (TDR-TB). 5,6 Ao longo dos últimos anos, é possível constatar algumas evoluções no desenvolvimento de compostos candidatos a fármacos que possam atuar contra a TB. 7 Após um intervalo de mais de 50 anos sem novos medicamentos para o tratamento da TB, a bedaquilina foi aprovada em 2012 pela agência norte-americana U.S. Food and Drug Administration (FDA) para o tratamento de MDR-TB. Atualmente, diversos candidatos a fármacos estão em estudos clínicos, [8][9][10][11][12] 39 Atualmente, diversos métodos e estratégias são utilizados para o desenvolvimento de novos fármacos contra a TB, como por exemplo: 1) abordagens genéticas para identificação de novos alvos; 2) ensaios de triagem em larga escala utilizando a micobactéria como plataforma; 3) ferramentas de biologia estrutural e triagem virtual e; 4) modificações ...

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“…The branched-chain amino acids are synthesized by plants, algae, fungi, bacteria and archaea, but not by animals, therefore are potential targets for the development of herbicides (McCourt and Duggleby, 2006). Worldwide, herbicides inhibiting acetolactatesynthase (ALS) are the most used ones at present.…”

Section: Weed Resistance To Acetolactate Synthase-inhibiting Herbicidesmentioning

confidence: 99%

Weed Resistance to Herbicides in the Czech Republic: History, Occurrence, Detection and Management

Hamouzová¹,

Salava²,

Soukup³

et al. 2011

Herbicides - Mechanisms and Mode of Action

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Acetohydroxyacid synthase and its role in the biosynthetic pathway for branched-chain amino acids

Cited by 198 publications

References 242 publications

Inhibitors of Bacillus anthracis acetohydroxyacid synthase

Inhibitors of Bacillus anthracis acetohydroxyacid synthase

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

Weed Resistance to Herbicides in the Czech Republic: History, Occurrence, Detection and Management

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