Home LiteratureArticle Details
PMID: 1396560 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

A novel antifolate resistance gene on the amplified H circle of Leishmania.

The EMBO journal ·Vol. 11 ·No. 10 ·1992-10-00 ·Pages 3601-8

Papadopoulou B, Roy G, Ouellette M

Abstract

In several Leishmania spp., resistance to methotrexate and other drugs is often associated with amplification of the chromosomal H region in the form of extrachromosomal H circles. We report here that the H circle of Leishmania tarentolae contains an 867 bp open reading frame, ltdh, which mediates high levels of resistance to methotrexate and other antifolates, after transfection. The predicted amino acid sequence of the ltdh gene product has significant similarities to a family of short-chain dehydrogenases, enzymes that are involved in several oxido-reduction reactions in a wide range of organisms. To resist antifolates, Leishmania amplifies the ltdh gene as part of the H circle. We propose that LTDH might be involved in an alternative pathway for the synthesis of reduced folates and that ltdh overproduction represents a novel mechanism for resistance to antifolates. Our results support the hypothesis that the H region of the Leishmania genome contains several drug resistance genes and that preferential amplification of this region has evolved as a defense mechanism against cytotoxic drugs.

Related Genes
ltdh
MeSH Terms
Amino Acid Sequence Animals Base Sequence Chromosome Mapping DNA, Protozoan/genetics,isolation & purification Drug Resistance/genetics Folic Acid Antagonists/pharmacology Leishmania/drug effects,enzymology,genetics Methotrexate/pharmacology Molecular Sequence Data Oligodeoxyribonucleotides Open Reading Frames Oxidoreductases/genetics Polymerase Chain Reaction Restriction Mapping Sequence Homology, Amino Acid Transfection
Chemicals
DNA, Protozoan Folic Acid Antagonists Oligodeoxyribonucleotides Oxidoreductases pteridine reductase Methotrexate
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Papadopoulou B
Service d'Infectiologie, CHUL, Sainte-Foy, Québec, Canada.
Roy G
Ouellette M
References (35)
35 references, click to expand
  1. Three-dimensional structure of holo 3 alpha,20 beta-hydroxysteroid dehydrogenase: a member of a short-chain dehydrogenase family.
    Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10064-8 PMID: 1946424
  2. Methotrexate-resistant Leishmania donovani genetically deficient in the folate-methotrexate transporter.
    J Biol Chem. 1988 May 25;263(15):7020-8 PMID: 3366764
  3. Targeted insertion of the neomycin phosphotransferase gene into the tubulin gene cluster of Trypanosoma brucei.
    Nature. 1990 Nov 8;348(6297):174-5 PMID: 2172836
  4. Stable expression of the bacterial neor gene in Leishmania enriettii.
    Nature. 1990 Feb 8;343(6258):572-4 PMID: 2300209
  5. A growth factor-repressible gene associated with protein kinase C-mediated inhibition of adipocyte differentiation.
    J Cell Biol. 1988 Jul;107(1):279-86 PMID: 2455724
  6. Wild-type and drug-resistant Leishmania major hydrolyze methotrexate to N-10-methyl-4-deoxy-4-aminopteroate without accumulation of methotrexate polyglutamates.
    J Biol Chem. 1989 Sep 25;264(27):15960-6 PMID: 2476435
  7. H DNA amplification in Leishmania resistant to both arsenite and methotrexate.
    Mol Biochem Parasitol. 1989 May 1;34(2):189-91 PMID: 2710170
  8. Nucleotide sequence of Rhizobium meliloti RCR2011 genes involved in host specificity of nodulation.
    Nucleic Acids Res. 1986 Sep 25;14(18):7453-72 PMID: 3020515
  9. The H circles of Leishmania tarentolae are a unique amplifiable system of oligomeric DNAs associated with drug resistance.
    J Biol Chem. 1988 Nov 15;263(32):16977-83 PMID: 3182827
  10. Crystal structure of a novel trimethoprim-resistant dihydrofolate reductase specified in Escherichia coli by R-plasmid R67.
    Biochemistry. 1986 Jul 29;25(15):4194-204 PMID: 3530319
  11. Activation of trypanosome surface glycoprotein genes involves a duplication-transposition leading to an altered 3' end.
    Cell. 1981 Dec;27(3 Pt 2):497-505 PMID: 6101223
  12. Unstable DNA amplifications in methotrexate-resistant Leishmania consist of extrachromosomal circles which relocalize during stabilization.
    Cell. 1984 Sep;38(2):431-9 PMID: 6467372
  13. Gene expression in Leishmania: analysis of essential 5' DNA sequences.
    Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2703-7 PMID: 1557376
  14. Direct and inverted DNA repeats associated with P-glycoprotein gene amplification in drug resistant Leishmania.
    EMBO J. 1991 Apr;10(4):1009-16 PMID: 1672636
  15. Drug resistance and P-glycoprotein gene amplification in the protozoan parasite Leishmania.
    Res Microbiol. 1991 Jul-Aug;142(6):737-46 PMID: 1961984
  16. Reductions in methotrexate and folate influx in methotrexate-resistant lines of Leishmania major are independent of R or H region amplification.
    J Biol Chem. 1987 Oct 5;262(28):13501-6 PMID: 3654626
  17. Extended superfamily of short alcohol-polyol-sugar dehydrogenases: structural similarities between glucose and ribitol dehydrogenases.
    FEBS Lett. 1984 Jan 9;165(2):190-6 PMID: 6420186
  18. A comprehensive set of sequence analysis programs for the VAX.
    Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387-95 PMID: 6546423
  19. Overproduction of a bifunctional thymidylate synthetase-dihydrofolate reductase and DNA amplification in methotrexate-resistant Leishmania tropica.
    Proc Natl Acad Sci U S A. 1983 Apr;80(8):2132-6 PMID: 6572966
  20. DNA sequencing with chain-terminating inhibitors.
    Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463-7 PMID: 271968
  21. Gene amplification in Leishmania.
    Annu Rev Microbiol. 1991;45:417-44 PMID: 1741620
  22. Characteristics of short-chain alcohol dehydrogenases and related enzymes.
    Eur J Biochem. 1991 Sep 1;200(2):537-43 PMID: 1889416
  23. Heavy metal resistance: a new role for P-glycoproteins in Leishmania.
    J Biol Chem. 1991 Oct 5;266(28):18427-30 PMID: 1680861
  24. Site-directed mutagenesis of the conserved tyrosine 151 of human placental NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase yields a catalytically inactive enzyme.
    Biochem Biophys Res Commun. 1991 Apr 30;176(2):840-5 PMID: 2025296
  25. Pseudomonas 3 beta-hydroxysteroid dehydrogenase. Primary structure and relationships to other steroid dehydrogenases.
    Eur J Biochem. 1991 Apr 23;197(2):359-65 PMID: 2026158
  26. The presence and distribution of reduced folates in Escherichia coli dihydrofolate reductase mutants.
    J Biol Chem. 1990 Jun 15;265(17):9850-6 PMID: 2190985
  27. Stable transfection of the human parasite Leishmania major delineates a 30-kilobase region sufficient for extrachromosomal replication and expression.
    Mol Cell Biol. 1990 Mar;10(3):1084-94 PMID: 2304458
  28. Purification and structural characterization of placental NAD(+)-linked 15-hydroxyprostaglandin dehydrogenase. The primary structure reveals the enzyme to belong to the short-chain alcohol dehydrogenase family.
    Biochemistry. 1990 Jan 23;29(3):738-43 PMID: 2337593
  29. Nucleotide sequence, transcription and deduced function of a gene involved in polyketide antibiotic synthesis in Streptomyces coelicolor.
    Gene. 1988 Dec 30;74(2):305-20 PMID: 2469622
  30. Toluene degradation by Pseudomonas putida F1. Nucleotide sequence of the todC1C2BADE genes and their expression in Escherichia coli.
    J Biol Chem. 1989 Sep 5;264(25):14940-6 PMID: 2670929
  31. Multiple drug resistance and conservative amplification of the H region in Leishmania major.
    J Biol Chem. 1989 Sep 5;264(25):15094-103 PMID: 2768255
  32. DNA amplification in arsenite-resistant Leishmania.
    Exp Cell Res. 1989 Jan;180(1):161-70 PMID: 2909386
  33. Extrachromosomal elements in the lower eukaryote Leishmania.
    J Biol Chem. 1988 Nov 15;263(32):16970-6 PMID: 3182826
  34. Amplified DNAs in laboratory stocks of Leishmania tarentolae: extrachromosomal circles structurally and functionally similar to the inverted-H-region amplification of methotrexate-resistant Leishmania major.
    Mol Cell Biol. 1988 Dec;8(12):5188-99 PMID: 3244352
  35. The amplified H circle of methotrexate-resistant leishmania tarentolae contains a novel P-glycoprotein gene.
    EMBO J. 1990 Apr;9(4):1027-33 PMID: 1969794
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1992-10-00
Pages
3601-8
Language
English
Region
England
NLM ID
8208664
PMCID
PMC556819
Subset
IM
Databases
GENBANK
S43129, X66358, X66359, X66360, X66361, X66362, X66363, X66364, X66365, Z11978
External Links
PubMed source PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2