Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid

Argyrides Argyrou, Matthew W. Vetting, Bola Aladegbami, John S. Blanchard

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

Isoniazid is a key drug used in the treatment of tuberculosis. Isoniazid is a pro-drug, which, after activation by the katG-encoded catalase peroxidase, reacts nonenzymatically with NAD+ and NADP+ to generate several isonicotinoyl adducts of these pyridine nucleotides. One of these, the acyclic 4S isomer of isoniazid-NAD, targets the inhA-encoded enoyl-ACP reductase, an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis. Here we show that the acyclic 4R isomer of isoniazid-NADP inhibits the M. tuberculosis dihydrofolate reductase (DHFR), an enzyme essential for nucleic acid synthesis. This biologically relevant form of the isoniazid adduct is a subnanomolar bisubstrate inhibitor of M. tuberculosis DHFR. Expression of M. tuberculosis DHFR in Mycobacterium smegmatis mc2155 protects cells against growth inhibition by isoniazid by sequestering the drug. Thus, M. tuberculosis DHFR is the first new target for isoniazid identified in the last decade.

Original languageEnglish (US)
Pages (from-to)408-413
Number of pages6
JournalNature Structural and Molecular Biology
Volume13
Issue number5
DOIs
StatePublished - May 14 2006

Fingerprint

Tetrahydrofolate Dehydrogenase
Isoniazid
Mycobacterium tuberculosis
NADP
NAD
Mycolic Acids
Mycobacterium smegmatis
Prodrugs
Enzymes
Pharmaceutical Preparations
Catalase
Nucleic Acids
Peroxidase
Oxidoreductases
Tuberculosis
Nucleotides
Growth

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid. / Argyrou, Argyrides; Vetting, Matthew W.; Aladegbami, Bola; Blanchard, John S.

In: Nature Structural and Molecular Biology, Vol. 13, No. 5, 14.05.2006, p. 408-413.

Research output: Contribution to journalArticle

Argyrou, Argyrides ; Vetting, Matthew W. ; Aladegbami, Bola ; Blanchard, John S. / Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid. In: Nature Structural and Molecular Biology. 2006 ; Vol. 13, No. 5. pp. 408-413.
@article{1f784d00893243aaa530c171c663103b,
title = "Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid",
abstract = "Isoniazid is a key drug used in the treatment of tuberculosis. Isoniazid is a pro-drug, which, after activation by the katG-encoded catalase peroxidase, reacts nonenzymatically with NAD+ and NADP+ to generate several isonicotinoyl adducts of these pyridine nucleotides. One of these, the acyclic 4S isomer of isoniazid-NAD, targets the inhA-encoded enoyl-ACP reductase, an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis. Here we show that the acyclic 4R isomer of isoniazid-NADP inhibits the M. tuberculosis dihydrofolate reductase (DHFR), an enzyme essential for nucleic acid synthesis. This biologically relevant form of the isoniazid adduct is a subnanomolar bisubstrate inhibitor of M. tuberculosis DHFR. Expression of M. tuberculosis DHFR in Mycobacterium smegmatis mc2155 protects cells against growth inhibition by isoniazid by sequestering the drug. Thus, M. tuberculosis DHFR is the first new target for isoniazid identified in the last decade.",
author = "Argyrides Argyrou and Vetting, {Matthew W.} and Bola Aladegbami and Blanchard, {John S.}",
year = "2006",
month = "5",
day = "14",
doi = "10.1038/nsmb1089",
language = "English (US)",
volume = "13",
pages = "408--413",
journal = "Nature Structural and Molecular Biology",
issn = "1545-9993",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid

AU - Argyrou, Argyrides

AU - Vetting, Matthew W.

AU - Aladegbami, Bola

AU - Blanchard, John S.

PY - 2006/5/14

Y1 - 2006/5/14

N2 - Isoniazid is a key drug used in the treatment of tuberculosis. Isoniazid is a pro-drug, which, after activation by the katG-encoded catalase peroxidase, reacts nonenzymatically with NAD+ and NADP+ to generate several isonicotinoyl adducts of these pyridine nucleotides. One of these, the acyclic 4S isomer of isoniazid-NAD, targets the inhA-encoded enoyl-ACP reductase, an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis. Here we show that the acyclic 4R isomer of isoniazid-NADP inhibits the M. tuberculosis dihydrofolate reductase (DHFR), an enzyme essential for nucleic acid synthesis. This biologically relevant form of the isoniazid adduct is a subnanomolar bisubstrate inhibitor of M. tuberculosis DHFR. Expression of M. tuberculosis DHFR in Mycobacterium smegmatis mc2155 protects cells against growth inhibition by isoniazid by sequestering the drug. Thus, M. tuberculosis DHFR is the first new target for isoniazid identified in the last decade.

AB - Isoniazid is a key drug used in the treatment of tuberculosis. Isoniazid is a pro-drug, which, after activation by the katG-encoded catalase peroxidase, reacts nonenzymatically with NAD+ and NADP+ to generate several isonicotinoyl adducts of these pyridine nucleotides. One of these, the acyclic 4S isomer of isoniazid-NAD, targets the inhA-encoded enoyl-ACP reductase, an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis. Here we show that the acyclic 4R isomer of isoniazid-NADP inhibits the M. tuberculosis dihydrofolate reductase (DHFR), an enzyme essential for nucleic acid synthesis. This biologically relevant form of the isoniazid adduct is a subnanomolar bisubstrate inhibitor of M. tuberculosis DHFR. Expression of M. tuberculosis DHFR in Mycobacterium smegmatis mc2155 protects cells against growth inhibition by isoniazid by sequestering the drug. Thus, M. tuberculosis DHFR is the first new target for isoniazid identified in the last decade.

UR - http://www.scopus.com/inward/record.url?scp=33745094315&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745094315&partnerID=8YFLogxK

U2 - 10.1038/nsmb1089

DO - 10.1038/nsmb1089

M3 - Article

C2 - 16648861

AN - SCOPUS:33745094315

VL - 13

SP - 408

EP - 413

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

SN - 1545-9993

IS - 5

ER -