Biochemical and structural characterization of CYP124: a methyl-branched lipid omega-hydroxylase from Mycobacterium tuberculosis.

Proceedings of the National Academy of Sciences of the United States of America
Jonathan B JohnstonPaul R Ortiz de Montellano

Abstract

Mycobacterium tuberculosis (Mtb) produces a variety of methyl-branched lipids that serve important functions, including modulating the immune response during pathogenesis and contributing to a robust cell wall that is impermeable to many chemical agents. Here, we report characterization of Mtb CYP124 (Rv2266) that includes demonstration of preferential oxidation of methyl-branched lipids. Spectrophotometric titrations and analysis of reaction products indicate that CYP124 tightly binds and hydroxylates these substrates at the chemically disfavored omega-position. We also report X-ray crystal structures of the ligand-free and phytanic acid-bound protein at a resolution of 1.5 A and 2.1 A, respectively, which provide structural insights into a cytochrome P450 with predominant omega-hydroxylase activity. The structures of ligand-free and substrate-bound CYP124 reveal several differences induced by substrate binding, including reorganization of the I helix and closure of the active site by elements of the F, G, and D helices that bind the substrate and exclude solvent from the hydrophobic active site cavity. The observed regiospecific catalytic activity suggests roles of CYP124 in the physiological oxidation of relevant Mtb methyl-...Continue Reading

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Citations

Jan 19, 2011·Metallomics : Integrated Biometal Science·Max J Cryle
Sep 17, 2010·The Journal of Biological Chemistry·Jonathan B JohnstonPaul R Ortiz de Montellano
Aug 9, 2011·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Ruimin ZhouLuet-Lok Wong
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Mar 24, 2016·Journal of Medicinal Chemistry·Madeline E KavanaghChris Abell
Sep 24, 2013·Archives of Biochemistry and Biophysics·Saurabh BhattaraiTae-Jin Oh
May 24, 2012·Biochemical Society Transactions·Sean A HudsonChris Abell
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Dec 22, 2016·British Journal of Pharmacology·Areej Abuhammad
Nov 9, 2018·The Biochemical Journal·Craig S RobbJan-Hendrik Hehemann
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Aug 24, 2018·Applied Microbiology and Biotechnology·Sandra Ortega UgaldeJ Chris Vos
Jul 22, 2015·The Journal of Biological Chemistry·Paul R Ortiz de Montellano
Oct 22, 2020·International Journal of Molecular Sciences·Sergey BukhdrukerNatallia Strushkevich
Sep 23, 2020·Journal of Microbiology and Biotechnology·Hemraj RimalTae-Jin Oh
Dec 29, 2020·Journal of Molecular Biology·Tatsiana VaraksaNatallia Strushkevich
Aug 24, 2010·Archives of Biochemistry and Biophysics·Jonathan B JohnstonPaul R Ortiz de Montellano
Jun 25, 2015·Microbiology Spectrum·Mamadou DafféMary Jackson
Jul 22, 2021·Bioorganic & Medicinal Chemistry·Luz Díaz-StoraniGuillermo R Labadie

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