title: Revisiting purine-histidine cross-pathway regulation in Saccharomyces cerevisiae: a central role for a small molecule.
abstract: Because some metabolic intermediates are involved in more than one pathway, crosstalk between pathways is crucial to maintaining homeostasis. AMP and histidine biosynthesis pathways are coregulated at the transcriptional level in response to adenine availability. 5'-Phosphoribosyl-4-carboxamide-5-aminoimidazole (AICAR), a metabolic intermediate at the crossroads between these two pathways, is shown here to be critical for activation of the transcriptional response in the absence of adenine. In this study, we show that both AMP and histidine pathways significantly contribute to AICAR synthesis. Furthermore, we show that upregulation of the histidine pathway clearly interferes with regulation of the AMP pathway, thus providing an explanation for the regulatory crosstalk between these pathways. Finally, we revisit the histidine auxotrophy of ade3 or ade16 ade17 mutants. Interestingly, overexpression of PMU1, encoding a potential phosphomutase, partially suppresses the histidine requirement of an ade3 ade16 ade17 triple mutant, most probably by reducing the level of AICAR in this mutant. Together our data clearly establish that AICAR is not just a metabolic intermediate but also acts as a true regulatory molecule.
authors.affiliation: Institut de Biochimie et Génétique Cellulaires, Université Bordeaux 2, CNRS UMR 5095, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Rébora
authors.forename: Benoît
authors.initials: B
authors.lastname: Laloo
authors.forename: Bertrand
authors.initials: B
authors.lastname: Daignan-Fornier
mesh_terms: D000249:Adenosine Monophosphate / Q000096:biosynthesis; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000633:toxicity; D005492:Folic Acid / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000502:physiology; D006639:Histidine / Q000378:metabolism*; D007291:Inosine Monophosphate / Q000378:metabolism; D011687:Purines / Q000378:metabolism*; D012265:Ribonucleotides / Q000502:physiology* / Q000633:toxicity; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*
chemical_list: D011687:Purines; D012265:Ribonucleotides; D007291:Inosine Monophosphate; D000620:Aminoimidazole Carboxamide; D000249:Adenosine Monophosphate; D006639:Histidine; D005492:Folic Acid; C031143:AICA ribonucleotide; C020635:SAICAR
references.citation: Yeast. 1997 Jul;13(9):837-48
references.pmid: 9234672
references.citation: Yeast. 1997 Jun 15;13(7):647-53
references.pmid: 9200814
references.citation: Yeast. 1998 Jan 30;14(2):115-32
references.pmid: 9483801
references.citation: Biochem Biophys Res Commun. 1998 Feb 24;243(3):821-6
references.pmid: 9500985
references.citation: Mol Microbiol. 1998 Nov;30(3):557-66
references.pmid: 9822821
references.citation: Mol Cell Biol. 1999 Jan;19(1):882-8
references.pmid: 9858611
references.citation: J Biol Chem. 1962 Dec;237:3725-30
references.pmid: 13977021
references.citation: J Biol Chem. 1962 Dec;237:3731-6
references.pmid: 13977022
references.citation: Mol Cell Biol. 2001 Dec;21(23):7901-12
references.pmid: 11689683
references.citation: J Biol Chem. 2000 Jul 7;275(27):20920-7
references.pmid: 10877846
references.citation: Hum Mol Genet. 2000 Sep 1;9(14):2159-65
references.pmid: 10958654
references.citation: Nucleic Acids Res. 2001 Jan 15;29(2):527-35
references.pmid: 11139623
references.citation: Fungal Genet Biol. 2001 Feb;32(1):21-31
references.pmid: 11277623
references.citation: Yeast. 2002 Jan 30;19(2):115-22
references.pmid: 11788966
references.citation: J Biol Chem. 2002 Jun 7;277(23):20205-13
references.pmid: 11923304
references.citation: Curr Genet. 2003 Apr;43(1):62-9
references.pmid: 12684846
references.citation: Am J Hum Genet. 2004 Jun;74(6):1276-81
references.pmid: 15114530
references.citation: Science. 2004 Jun 11;304(5677):1644-7
references.pmid: 15192221
references.citation: Basic Life Sci. 1973;2:85-95
references.pmid: 4599853
references.citation: Genetics. 1979 May;92(1):1-15
references.pmid: 387516
references.citation: J Bacteriol. 1980 Dec;144(3):1068-75
references.pmid: 7002904
references.citation: Lancet. 1984 Nov 10;2(8411):1058-61
references.pmid: 6150139
references.citation: Gene. 1986;45(3):299-310
references.pmid: 3026915
references.citation: Science. 1987 Aug 21;237(4817):874-80
references.pmid: 3303332
references.citation: Microbiol Rev. 1988 Jun;52(2):248-73
references.pmid: 3045517
references.citation: Mol Cell Biol. 1990 Feb;10(2):643-52
references.pmid: 2405251
references.citation: Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6746-50
references.pmid: 1495962
references.citation: Science. 1992 Nov 13;258(5085):1143-5
references.pmid: 1439822
references.citation: Biochem Biophys Res Commun. 1994 May 16;200(3):1551-6
references.pmid: 8185610
references.citation: Mol Cell Biol. 1994 Oct;14(10):6411-8
references.pmid: 7935367
references.citation: Eur J Biochem. 1995 Apr 15;229(2):558-65
references.pmid: 7744080
references.citation: FEMS Microbiol Lett. 1995 May 1;128(2):201-6
references.pmid: 7538479
references.citation: Genetics. 1996 Feb;142(2):371-81
references.pmid: 8852837
references.citation: Genetics. 1996 Nov;144(3):923-33
references.pmid: 8913738
references.citation: J Biol Chem. 1996 Nov 22;271(47):29637-43
references.pmid: 8939895
references.citation: Genetics. 1997 Oct;147(2):383-97
references.pmid: 9335580