Acetyl‐coenzyme A carboxylases: Versatile targets for drug discovery

Grass weed populations resistant to aryloxyphenoxypropionate (APP) and cyclohexanedione herbicides that inhibit acetyl-CoA carboxylase (ACCase; EC 6.4.1.2) represent a major problem for sustainable agriculture. We investigated the molecular basis of resistance to ACCase-inhibiting herbicides for nine wild oat (Avena sterilis ssp. ludoviciana Durieu) populations from the northern grain-growing region of Australia. Five amino acid substitutions in plastid ACCase were correlated with herbicide resistance: Ile-1,781-Leu, Trp-1,999-Cys, Trp-2,027-Cys, Ile-2,041-Asn, and Asp-2,078-Gly (numbered according to the Alopecurus myosuroides plastid ACCase). An allele-specific PCR test was designed to determine the prevalence of these five mutations in wild oat populations suspected of harboring ACCase-related resistance with the result that, in most but not all cases, plant resistance was correlated with one (and only one) of the five mutations. We then showed, using a yeast gene-replacement system, that these single-site mutations also confer herbicide resistance to wheat plastid ACCase: Ile-1,781-Leu and Asp-2,078-Gly confer resistance to APPs and cyclohexanediones, Trp-2,027-Cys and Ile-2,041-Asn confer resistance to APPs, and Trp-1,999-Cys confers resistance only to fenoxaprop. These mutations are very likely to confer resistance to any grass weed species under selection imposed by the extensive agricultural use of the herbicides.aryloxyphenoxypropionate ͉ Avena ͉ cyclohexanedione

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“…1 contains all of the residues shown to be present in the APP-binding pocket as well as residues of the CoA-binding site (4,16) (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

Single-site mutations in the carboxyltransferase domain of plastid acetyl-CoA carboxylase confer resistance to grass-specific herbicides

Liu

Harrison²,

Chalupská³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

148

176

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“…The functions of those enzymes in cellular biochemistry and human physiology are complex and cannot be limited to simply providing malonyl-CoA for FA production. The defects in their activity or their genes expression are associated with various diseases such as obesity, insulin resistance and diabetes as well as heart disease and cancer (Tong and Harwood, 2006;Folmes and Lopaschuk, 2007). One of the proposed medical applications of the enzymes depends on their inhibition, which is associated with inhibition of fatty acids synthesis and stimulation of fatty acids oxidation, and which, in consequence, might reduce cardiovascular risk in metabolic syndrome.…”

Section: Human Accase As Target In Diseases Treatmentmentioning

confidence: 99%

OPINIONS Acetyl-coenzyme A carboxylase – an attractive enzyme for biotechnology

Podkowiński¹,

Tworak²

2011

bta

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Acetyl-CoA carboxylase catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. This reaction constitutes the first committed step of fatty acid synthesis in most organisms, while its product also serves as a universal precursor for various other high-value compounds. The important regulatory and rate-limiting role of acetyl-CoA carboxylase makes this enzyme a powerful tool in a variety of biotechnological and medical projects. This review presents the current knowledge on structural and functional features of the enzyme and focuses on its divergent applications. Different metabolic engineering attempts that lead to the production of various compounds, such as fatty acids, polyketides or flavonoids, are presented and their advantages and limitations discussed. The importance of studies on acetyl-CoA carboxylase activity for design and development of new herbicides and antibiotics as well as for medical intervention is also highlighted. Acetyl-coenzyme A carboxylase -enzyme architecture, biochemistry and its role in cell physiologyA variety of biotechnological projects targeted to modulate acetyl-coenzyme A carboxylase activity in bacteria, plants and humans have been proposed and experimentally tested. Here, we would like to present a comprehensive review of these strategies together with a survey of the potential of acetyl-CoA carboxylase for biotechnology.Acetyl-coenzyme A carboxylase (ACC, E.C.6.4.1.2), recognized as an essential enzyme for all Eukaryotes and the majority of Bacteria, is responsible for carboxylation of acetyl-CoA that results in malonyl-coenzyme A formation (Fig. 1). Malonyl-CoA is a major building block for compounds such as fatty acids, polyketides and flavonoids -important components for cell growth, as well as for food, pharmaceuticals and energy production.The malonyl-CoA synthesis consists of two half-reactions (Nikolau et al., 2003). The first one, adenosine triphosphate-dependent carboxylation of biotin prosthetic group covalently bound to a module named biotin carboxyl carrier protein (BCCP), is catalyzed by ACCase segment of biotin carboxylase activity (BC) (Fig. 2). This reaction is immediately followed by the second half-re action: the transfer of a carboxyl group from carboxylated biotin to acetyl-CoA, resulting in malonyl-CoA formation. Carboxyl transferase (CT) is a module that catalyzes the second reaction and provides the required specificity in recognition of the carboxyl acceptor (acetyl-CoA). The ACCase model usually presents BCCP, a module with covalently attached biotin, as a beam responsible for biotin dislocation between two active centers -one with BT and the other with CT activity. The three (Fig. 3). The prokaryotic and eukaryotic types of ACCases are evolutionary related and the phylogeny of the modules provides some hints about their cenancestor, a split between Archaea and Bacteria, and arising of Eukaryota (Lombard and Moreira, 2011).Phylogeny is out of scope of this manuscript, but acetyl-coenzyme A carboxylases from various organisms representing v...

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“…In yeast, which can take up long-chain fatty acids from the medium, the ACC1 gene remains essential as well. The essential nature and central role in cellular metabolism makes ACC a potentially valuable target for new drugs (1).…”

Section: Fatty Acid Metabolism | Human Healthmentioning

confidence: 99%

Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity

Marjanovic

Chalupská

Patenode

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Acetyl-CoA carboxylase (ACC) is a key enzyme of fatty acid metabolism with multiple isozymes often expressed in different eukaryotic cellular compartments. ACC-made malonyl-CoA serves as a precursor for fatty acids; it also regulates fatty acid oxidation and feeding behavior in animals. ACC provides an important target for new drugs to treat human diseases. We have developed an inexpensive nonradioactive high-throughput screening system to identify new ACC inhibitors. The screen uses yeast gene-replacement strains depending for growth on cloned human ACC1 and ACC2. In "proof of concept" experiments, growth of such strains was inhibited by compounds known to target human ACCs. The screen is sensitive and robust. Medium-size chemical libraries yielded new specific inhibitors of human ACC2. The target of the best of these inhibitors was confirmed with in vitro enzymatic assays. This compound is a new drug chemotype inhibiting human ACC2 with 2.8 μM IC 50 and having no effect on human ACC1 at 100 μM.fatty acid metabolism | human health

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Acetyl‐coenzyme A carboxylases: Versatile targets for drug discovery

Cited by 175 publications

References 41 publications

Single-site mutations in the carboxyltransferase domain of plastid acetyl-CoA carboxylase confer resistance to grass-specific herbicides

Single-site mutations in the carboxyltransferase domain of plastid acetyl-CoA carboxylase confer resistance to grass-specific herbicides

OPINIONS Acetyl-coenzyme A carboxylase – an attractive enzyme for biotechnology

Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity

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