Molecular Basis for the Inhibition of the Carboxyltransferase Domain of Acetyl-coenzyme-A Carboxylase by Haloxyfop and Diclofop

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2004 Apr 14

PMID 15079078

Citations 38

Authors

Hailong Zhang

Benjamin Tweel

Liang Tong

Affiliations

Soon will be listed here.

Abstract

Acetyl-CoA carboxylases (ACCs) are crucial for the metabolism of fatty acids, making these enzymes important targets for the development of therapeutics against obesity, diabetes, and other diseases. The carboxyltransferase (CT) domain of ACC is the site of action of commercial herbicides, such as haloxyfop, diclofop, and sethoxydim. We have determined the crystal structures at up to 2.5-A resolution of the CT domain of yeast ACC in complex with the herbicide haloxyfop or diclofop. The inhibitors are bound in the active site, at the interface of the dimer of the CT domain. Unexpectedly, inhibitor binding requires large conformational changes for several residues in this interface, which create a highly conserved hydrophobic pocket that extends deeply into the core of the dimer. Two residues that affect herbicide sensitivity are located in this binding site, and mutation of these residues disrupts the structure of the domain. Other residues in the binding site are strictly conserved among the CT domains.

Citing Articles

Structure of the endogenous insect acetyl-coA carboxylase carboxyltransferase domain.

Wang D, Bu F, Yang G, Brenke H, Liu B J Biol Chem. 2024; 300(10):107800.

PMID: 39305960 PMC: 11735997. DOI: 10.1016/j.jbc.2024.107800.

Target-site mutations Ile1781Leu and Ile2041Asn in the gene confer resistance to fluazifop-p-butyl and pinoxaden herbicides in a johnsongrass accession from Arkansas, USA.

Gonzalez-Torralva F, Norsworthy J Plant Direct. 2024; 8(3):e576.

PMID: 38516339 PMC: 10955616. DOI: 10.1002/pld3.576.

Sequence and structural similarities of ACCase protein of and wheat: An insight to explain herbicide selectivity.

Rajak B, Rani P, Singh N, Singh D Front Plant Sci. 2023; 13:1056474.

PMID: 36684777 PMC: 9845919. DOI: 10.3389/fpls.2022.1056474.

Diverse mechanisms associated with cyhalofop-butyl resistance in Chinese sprangletop ( (L.) Nees): Characterization of target-site mutations and metabolic resistance-related genes in two resistant populations.

Zhang Y, Chen L, Song W, Cang T, Xu M, Wu C Front Plant Sci. 2022; 13:990085.

PMID: 36518516 PMC: 9742530. DOI: 10.3389/fpls.2022.990085.

Mining Fatty Acid Biosynthesis for New Antimicrobials.

Radka C, Rock C Annu Rev Microbiol. 2022; 76:281-304.

PMID: 35650664 PMC: 9463108. DOI: 10.1146/annurev-micro-041320-110408.

References

Zuther E, Johnson J, Haselkorn R, McLeod R, Gornicki P . Growth of Toxoplasma gondii is inhibited by aryloxyphenoxypropionate herbicides targeting acetyl-CoA carboxylase. Proc Natl Acad Sci U S A. 1999; 96(23):13387-92. PMC: 23957. DOI: 10.1073/pnas.96.23.13387. View

Ramsay R, Gandour R, van der Leij F . Molecular enzymology of carnitine transfer and transport. Biochim Biophys Acta. 2001; 1546(1):21-43. DOI: 10.1016/s0167-4838(01)00147-9. View

Matzuk M, WAKIL S . Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science. 2001; 291(5513):2613-6. DOI: 10.1126/science.1056843. View

Zagnitko O, Jelenska J, Tevzadze G, Haselkorn R, Gornicki P . An isoleucine/leucine residue in the carboxyltransferase domain of acetyl-CoA carboxylase is critical for interaction with aryloxyphenoxypropionate and cyclohexanedione inhibitors. Proc Natl Acad Sci U S A. 2001; 98(12):6617-22. PMC: 34402. DOI: 10.1073/pnas.121172798. View

Jogl G, Tao X, Xu Y, Tong L . COMO: a program for combined molecular replacement. Acta Crystallogr D Biol Crystallogr. 2001; 57(Pt 8):1127-34. DOI: 10.1107/s0907444901006783. View

Jelenska J, Sirikhachornkit A, Haselkorn R, Gornicki P . The carboxyltransferase activity of the apicoplast acetyl-CoA carboxylase of Toxoplasma gondii is the target of aryloxyphenoxypropionate inhibitors. J Biol Chem. 2002; 277(26):23208-15. DOI: 10.1074/jbc.M200455200. View

Cronan Jr J, Waldrop G . Multi-subunit acetyl-CoA carboxylases. Prog Lipid Res. 2002; 41(5):407-35. DOI: 10.1016/s0163-7827(02)00007-3. View

Lenhard J, Gottschalk W . Preclinical developments in type 2 diabetes. Adv Drug Deliv Rev. 2002; 54(9):1199-212. DOI: 10.1016/s0169-409x(02)00092-3. View

Hill J, Wyatt H, Reed G, Peters J . Obesity and the environment: where do we go from here?. Science. 2003; 299(5608):853-5. DOI: 10.1126/science.1079857. View

10.

Friedman J . A war on obesity, not the obese. Science. 2003; 299(5608):856-8. DOI: 10.1126/science.1079856. View

11.

Pi-Sunyer X . A clinical view of the obesity problem. Science. 2003; 299(5608):859-60. DOI: 10.1126/science.1082319. View

12.

Zhang H, Yang Z, Shen Y, Tong L . Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase. Science. 2003; 299(5615):2064-7. DOI: 10.1126/science.1081366. View

13.

Harwood Jr H, Petras S, Shelly L, Zaccaro L, Perry D, Makowski M . Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. J Biol Chem. 2003; 278(39):37099-111. DOI: 10.1074/jbc.M304481200. View

14.

Delye C, Zhang X, Chalopin C, Michel S, Powles S . An isoleucine residue within the carboxyl-transferase domain of multidomain acetyl-coenzyme A carboxylase is a major determinant of sensitivity to aryloxyphenoxypropionate but not to cyclohexanedione inhibitors. Plant Physiol. 2003; 132(3):1716-23. PMC: 167108. DOI: 10.1104/pp.103.021139. View

15.

Kemal C, Casida J . Coenzyme A esters of 2-aryloxyphenoxypropionate herbicides and 2-arylpropionate antiinflammatory drugs are potent and stereoselective inhibitors of rat liver acetyl-CoA carboxylase. Life Sci. 1992; 50(7):533-40. DOI: 10.1016/0024-3205(92)90393-4. View

16.

Nicholls A, Sharp K, Honig B . Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins. 1991; 11(4):281-96. DOI: 10.1002/prot.340110407. View

17.

Otwinowski Z, Minor W . Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 1997; 276:307-26. DOI: 10.1016/S0076-6879(97)76066-X. View

18.

Rendina A, Felts J, Beaudoin J, Look L, Paraskos S, Hagenah J . Kinetic characterization, stereoselectivity, and species selectivity of the inhibition of plant acetyl-CoA carboxylase by the aryloxyphenoxypropionic acid grass herbicides. Arch Biochem Biophys. 1988; 265(1):219-25. DOI: 10.1016/0003-9861(88)90387-6. View

19.

Guchhait R, Polakis S, Dimroth P, Stoll E, Moss J, Lane M . Acetyl coenzyme A carboxylase system of Escherichia coli. Purification and properties of the biotin carboxylase, carboxyltransferase, and carboxyl carrier protein components. J Biol Chem. 1974; 249(20):6633-45. View

20.

WAKIL S, STOOPS J, Joshi V . Fatty acid synthesis and its regulation. Annu Rev Biochem. 1983; 52:537-79. DOI: 10.1146/annurev.bi.52.070183.002541. View