{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T01:17:29Z","timestamp":1779326249838,"version":"3.51.4"},"reference-count":59,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5347","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[1998,1,2]]},"abstract":"<jats:p>\n            The preferred antitubercular drug isoniazid specifically targets a long-chain enoyl-acyl carrier protein reductase (InhA), an enzyme essential for mycolic acid biosynthesis in\n            <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n            . Despite the widespread use of this drug for more than 40 years, its precise mode of action has remained obscure. Data from x-ray crystallography and mass spectrometry reveal that the mechanism of isoniazid action against InhA is covalent attachment of the activated form of the drug to the nicotinamide ring of nicotinamide adenine dinucleotide bound within the active site of InhA.\n          <\/jats:p>","DOI":"10.1126\/science.279.5347.98","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T09:42:47Z","timestamp":1027762967000},"page":"98-102","source":"Crossref","is-referenced-by-count":583,"title":["Modification of the NADH of the Isoniazid Target (InhA) from\n            <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.1126","volume":"279","author":[{"given":"Denise A.","family":"Rozwarski","sequence":"first","affiliation":[{"name":"D. A. Rozwarski, Department of Biochemistry and Biophysics, Texas A&amp;M University, College Station, TX 77843, USA."},{"name":"G. A. Grant, Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"D. H. R. Barton, Department of Chemistry, Texas A&amp;M University, College Station, TX 77843, USA."},{"name":"W. R. Jacobs Jr., Department of Microbiology and Immunology and Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA."},{"name":"J. C. Sacchettini, Department of Biochemistry and Biophysics and Department of Chemistry, Texas A&amp;M University, College Station, TX 77843, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory A.","family":"Grant","sequence":"additional","affiliation":[{"name":"D. A. Rozwarski, Department of Biochemistry and Biophysics, Texas A&amp;M University, College Station, TX 77843, USA."},{"name":"G. A. Grant, Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"D. H. R. Barton, Department of Chemistry, Texas A&amp;M University, College Station, TX 77843, USA."},{"name":"W. R. Jacobs Jr., Department of Microbiology and Immunology and Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA."},{"name":"J. C. Sacchettini, Department of Biochemistry and Biophysics and Department of Chemistry, Texas A&amp;M University, College Station, TX 77843, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derek H. R.","family":"Barton","sequence":"additional","affiliation":[{"name":"D. A. Rozwarski, Department of Biochemistry and Biophysics, Texas A&amp;M University, College Station, TX 77843, USA."},{"name":"G. A. Grant, Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"D. H. R. Barton, Department of Chemistry, Texas A&amp;M University, College Station, TX 77843, USA."},{"name":"W. R. Jacobs Jr., Department of Microbiology and Immunology and Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA."},{"name":"J. C. Sacchettini, Department of Biochemistry and Biophysics and Department of Chemistry, Texas A&amp;M University, College Station, TX 77843, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"William R.","family":"Jacobs","sequence":"additional","affiliation":[{"name":"D. A. Rozwarski, Department of Biochemistry and Biophysics, Texas A&amp;M University, College Station, TX 77843, USA."},{"name":"G. A. Grant, Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"D. H. R. Barton, Department of Chemistry, Texas A&amp;M University, College Station, TX 77843, USA."},{"name":"W. R. 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Musser personal communication."},{"key":"e_1_3_1_19_2","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1126\/science.7886450","volume":"267","author":"Dessen A.","year":"1995","unstructured":"Dessen A., et al., Science 267, 1638 (1995).","journal-title":"Science"},{"key":"e_1_3_1_20_2","unstructured":"Isoniazid-inhibited InhA was produced by incubating at room temperature 350 \u03bcM InhA 17.5 mM NADH 35 mM isoniazid and 3.5 mM MnCl 2 buffered at pH 7.5 with 50 mM Hepes. Before InhA was added to the reaction mixture it was stored in 1 mM EDTA 1 mM dithiothreitol and 0.5 mM phenylmethylsulfonyl fluoride buffered at pH 7.5 with 50 mM Hepes. InhA activity was measured by removing aliquots from the incubation mixture and spectrophotometrically monitoring the turnover of fresh NADH to NAD + at 340 nm in the presence of a fatty acyl-CoA substrate (6). InhA activity decreased by 90% within 2 days and coincided with the reaction mixture turning bright yellow. Crystals of isoniazid-inhibited InhA were produced by combining the incubation mixture in a 1:1 ratio with 12% methyl pentane diol 4% dimethyl sulfoxide 100 mM Hepes at pH 7.5 and 50 mM sodium citrate at pH 6.5 and placing it in a hanging drop enclosure. Within a week crystals reached a size of 0.4 \u00d7 0.3 \u00d7 0.3 mm and were of the same morphology as those used previously to determine the native crystal structure (18)."},{"key":"e_1_3_1_21_2","unstructured":"A single crystal was used to collect a data set at room temperature with a MacScience DIP2030 image plate system with double-focusing mirrors coupled to a Rigaku x-ray generator using a copper rotating anode with a 0.005-mm nickel filter and a 0.5-mm x-ray beam collimator. The Denzo and Scalepack package (26) was used to autoindex integrate and scale frames of data. Data collection statistics are listed in Table 1."},{"key":"e_1_3_1_22_2","unstructured":"An initial difference Fourier ( F o \u2013 F c ) electron density map in which the calculated phases were derived from the native InhA model with bound NADH (PDB 1eny) contained a single intense peak (7\u03c3) with a size and shape distinctive of the isonicotinic acyl group derived from isoniazid. No other peaks existed in the map with the same intensity and characteristics. Refinement of the isoniazid-inhibited InhA model was performed with the X-PLOR software package (27) and a 2\u03c3 cutoff was applied to the structure factors resulting in less than 2% of the data being omitted. Several rounds of manual model building and automated refinement with addition of the isonicotinic-acyl group and 68 ordered water molecules brought the R factor to 20.2% and the R free to 29.7% for data from 10.0 to 2.7 \u00c5. Throughout this process the validity of the model was confirmed by inspecting simulated annealing omit maps in which either 10 contiguous residues or a 6 \u00c5 sphere was omitted. Model refinement statistics are listed in Table 1."},{"key":"e_1_3_1_23_2","unstructured":"Before mass spectrometry the isoniazid-inhibited InhA was separated from the other components of the reaction mixture (excess NADH isoniazid Mn 2+ ions) by using a Pharmacia Superdex-75 HR-10\/30 gel-filtration column equilibrated in 100 mM triethylammonium acetate pH 7.0 at a flow rate of 0.5 ml\/min. The fractions containing the isoniazid-inhibited InhA were pooled and concentrated to about 2 mg\/ml. An enzymatic activity assay confirmed that the purified protein was inactive which implies that the isonicotinic acyl-NADH was still bound to InhA. Portions of this enzyme preparation (10 to 20 \u03bcl) were brought to 100 \u03bcl with a solution of 50% methanol and 1% acetic acid in water. These dilutions were infused into a Finnigan LCQ electrospray mass spectrometer at 5 \u03bcl\/min. Spectra were analyzed in positive mode and averaged for 1 min. The mass value of 770 daltons obtained for the isonicotinic acyl-NADH present within the isoniazid-inhibited InhA sample corresponds to the addition of a mass fragment consisting of NADH with one hydrogen removed (mass = 664 daltons) plus a mass fragment consisting of an isonicotinic acyl group derived from isoniazid (mass = 106 daltons)."},{"key":"e_1_3_1_24_2","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1128\/AAC.27.3.399","volume":"27","author":"Shoeb H. A.","year":"1985","unstructured":"Shoeb H. A., et al., Antimicrob. Agents Chemother. 27, 399 (1985).","journal-title":"Antimicrob. Agents Chemother."},{"key":"e_1_3_1_25_2","unstructured":"Reaction mixtures containing Mn 2+ ions [ ring - 14 C]-isoniazid and NADH (or NAD + ) with and without InhA were applied to a Pharmacia Superdex-Peptide gel-filtration column and equilibrated in 50 mM Hepes pH 7.5 at a flow rate of 0.5 ml\/min. Each component of the starting mixture was separated and identified and the radioactivity of each column fraction was measured in a scintillation counter. Incubations that lack InhA do not shift any portion of the radiolabel from the isoniazid peak to an area of the chromatogram of larger molecular mass near the NADH peak."},{"key":"e_1_3_1_26_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5295.2107"},{"key":"e_1_3_1_27_2","unstructured":"Z. Otwinowski in Data Collection and Processing L. Sawyer N. Isaacs S. Bailey Eds. [Science and Engineering Research Council (SERC) Daresbury Laboratory Warrington UK 1993] pp. 56\u201362."},{"key":"e_1_3_1_28_2","unstructured":"A. T. Brunger X-PLOR version 3.1 A System for X-Ray Crystallography and NMR (Yale Univ. Press New Haven CT 1992)."},{"key":"e_1_3_1_29_2","doi-asserted-by":"crossref","unstructured":"F. Paoletti et al. Chem.-Biol. Interactions 76 3 (1990).","DOI":"10.1016\/0009-2797(90)90030-Q"},{"key":"e_1_3_1_30_2","unstructured":"E. Lewin and J. G. Hirsh Am. Rev. Tuberc. Pulm. Dis. 71 732 (1955);"},{"key":"e_1_3_1_30_3","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1042\/bj0730500","volume":"73","author":"Winder F. G.","year":"1959","unstructured":"Winder F. G., Denneny J. M., Biochem. J. 73, 500 (1959);","journal-title":"Biochem. 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Chem."},{"key":"e_1_3_1_33_2","unstructured":"Figure 1 was made with the program O version 5.9 (T. A. Jones and M. Kjeldgaard Uppsala University Uppsala Sweden). Figures 3 and 4 were made with Chemistry 4-D Draw (ChemInnovation Software San Diego CA) and Fig. 5 was made with INSIGHT II (Biosym Technologies San Diego CA)."},{"key":"e_1_3_1_34_2","unstructured":"Financial support was provided by the Welch Foundation and NIH grants GM-45859 and AI-36849. We thank C. Vilcheze and R. Bittman for supplying 2- trans -octenoyl-coenzymeA for InhA activity assays M. W. Crankshaw for mass spectrometry analysis members of the Center for Structural Biology at Texas A&M University () for helpful discussions and M. Edwards for manuscript preparation assistance. The coordinates have been deposited in the Protein Data Bank with entry number 1zid."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.279.5347.98","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T04:54:05Z","timestamp":1705121645000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.279.5347.98"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1998,1,2]]},"references-count":59,"journal-issue":{"issue":"5347","published-print":{"date-parts":[[1998,1,2]]}},"alternative-id":["10.1126\/science.279.5347.98"],"URL":"https:\/\/doi.org\/10.1126\/science.279.5347.98","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[1998,1,2]]}}}