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PMID: 1969794 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

The amplified H circle of methotrexate-resistant leishmania tarentolae contains a novel P-glycoprotein gene.

The EMBO journal ·Vol. 9 ·No. 4 ·1990-04-00 ·Pages 1027-33

Ouellette M, Fase-Fowler F, Borst P

Abstract

Acquired resistance to methotrexate in Leishmania species is often associated with the amplification of H circles, 68 kb duplex DNA circles containing a 30 kb inverted repeat. We report here that the H circle of Leishmania tarentolae contains an open reading frame, ltpgpA, that has the attributes of P-glycoproteins (large plasma membrane proteins known to extrude lipophilic drugs from mammalian cells). Although amplification of H circles is associated with proportionally increased levels of a 5.5 kb transcript of the ltpgpA gene, such methotrexate resistant mutants are not cross-resistant to any of the drugs extruded by mammalian multi-drug resistant cells. In Leishmania, ltpgpA is part of a gene family containing at least two other members. Sequences homologous to one of the nucleotide binding sites of ltpgpA are conserved in other kinetoplastida.

MeSH Terms
ATP Binding Cassette Transporter, Subfamily B, Member 1 ATP-Binding Cassette Transporters/genetics Algorithms Amino Acid Sequence Animals Base Sequence Drug Resistance/genetics Gene Amplification Genes Humans Leishmania/drug effects,genetics Membrane Glycoproteins/genetics Methotrexate/pharmacology Molecular Sequence Data Protein Conformation Protozoan Proteins Restriction Mapping Sequence Homology, Nucleic Acid
Chemicals
ATP Binding Cassette Transporter, Subfamily B, Member 1 ATP-Binding Cassette Transporters Membrane Glycoproteins PgpA protein, Leishmania Protozoan Proteins Methotrexate
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Ouellette M
Division of Molecular Biology, Netherlands Cancer Institute, Amsterdam.
Fase-Fowler F
Borst P
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37 references, click to expand
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1990-04-00
Pages
1027-33
Language
English
Region
England
NLM ID
8208664
PMCID
PMC551774
Subset
IM
Databases
GENBANK
X17154
External Links
PubMed source PMC Full Text View journal details
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