title: Role for human arylamine N-acetyltransferase 1 in the methionine salvage pathway.
abstract: The Phase II drug metabolizing enzyme arylamine N-acetyltransferase 1 (NAT1) has been implicated in the growth and survival of cancer cells, although the mechanisms that underlies these effects are unknown. Here, a focused metabolomics approach was used to identify changes in folate catabolism as well as the S-adenosylmethionine (SAM) cycle following NAT1 knockdown with shRNA. Although acetylation of the folate catabolite p-aminobenzoylglutamate (pABG) was significantly decreased, there were no changes in intracellular pABG or the various components of the SAM cycle. By contrast, the flux of homocysteine in the medium was different following NAT1 knockdown after the methionine content was exhausted suggesting a need for this metabolite in methionine synthesis. Analysis of the growth of various cancer cells in methylthioadenosine-supplemented medium showed that NAT1 knockdown inhibited the methionine salvage pathway in HT-29 cells but not in HeLa or MDA-MB-436 cells. The cause of this was a low level of expression of the isomerase MRI-1 in the HT-29 cells. Knocking down both NAT1 and MRI-1 in HeLa cells with siRNA further demonstrated a redundancy between these 2 enzymes, although direct isomerase activity by NAT1 could not be demonstrated. The present study has identified a novel endogenous role for human NAT1 that might explain some of its effects in cancer cell growth and survival.
authors.affiliation: Laboratory for Molecular and Cellular Pharmacology, School of Biomedical Sciences, University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Katey L
authors.initials: KL
authors.lastname: Witham
authors.affiliation: Laboratory for Molecular and Cellular Pharmacology, School of Biomedical Sciences, University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Rodney F
authors.initials: RF
authors.lastname: Minchin
authors.affiliation: Laboratory for Molecular and Cellular Pharmacology, School of Biomedical Sciences, University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia. Electronic address: n.butcher@uq.edu.au.
authors.forename: Neville J
authors.initials: NJ
authors.lastname: Butcher
mesh_terms: D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008715:Methionine / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D008715:Methionine; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1
keywords: Endogenous; Methionine; N-acetyltransferase; Salvage