The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals.

TitleThe human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals.
Publication TypeJournal Article
Year of Publication2001
AuthorsDolce, V, Fiermonte, G, Runswick, MJ, Palmieri, F, Walker, JE
JournalProc Natl Acad Sci U S A
Volume98
Issue5
Pagination2284-8
Date Published2001 Feb 27
ISSN0027-8424
KeywordsAmino Acid Sequence, Antiviral Agents, Base Sequence, Biological Transport, Carrier Proteins, DNA, Complementary, Humans, Membrane Transport Proteins, Mitochondria, Molecular Sequence Data, Recombinant Proteins, Zidovudine
Abstract

The synthesis of DNA in mitochondria requires the uptake of deoxynucleotides into the matrix of the organelle. We have characterized a human cDNA encoding a member of the family of mitochondrial carriers. The protein has been overexpressed in bacteria and reconstituted into phospholipid vesicles where it catalyzed the transport of all four deoxy (d) NDPs, and, less efficiently, the corresponding dNTPs, in exchange for dNDPs, ADP, or ATP. It did not transport dNMPs, NMPs, deoxynucleosides, nucleosides, purines, or pyrimidines. The physiological role of this deoxynucleotide carrier is probably to supply deoxynucleotides to the mitochondrial matrix for conversion to triphosphates and incorporation into mitochondrial DNA. The protein is expressed in all human tissues that were examined except for placenta, in accord with such a central role. The deoxynucleotide carrier also transports dideoxynucleotides efficiently. It is likely to be medically important by providing the means of uptake into mitochondria of nucleoside analogs, leading to the mitochondrial impairment that underlies the toxic side effects of such drugs in the treatment of viral illnesses, including AIDS, and in cancer therapy.

DOI10.1073/pnas.031430998
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
Citation Key10.1073/pnas.031430998
PubMed ID11226231
PubMed Central IDPMC30130