Structure of prokaryotic polyamine deacetylase reveals evolutionary functional relationships with eukaryotic histone deacetylases.
Polyamines are a ubiquitous class of polycationic small molecules that can influence gene expression by binding to nucleic acids. Reversible polyamine acetylation regulates nucleic acid binding and is required for normal cell cycle progression and proliferation. Here, we report the structures of Mycoplana ramosa acetylpolyamine amidohydrolase (APAH) complexed with a transition state analogue and a hydroxamate inhibitor and an inactive mutant complexed with two acetylpolyamine substrates. The structure of APAH is the first of a histone deacetylase-like oligomer and reveals that an 18-residue insert in the L2 loop promotes dimerization and the formation of an 18 Å long "L"-shaped active site tunnel at the dimer interface, accessible only to narrow and flexible substrates. The importance of dimerization for polyamine deacetylase function leads to the suggestion that a comparable dimeric or double-domain histone deacetylase could catalyze polyamine deacetylation reactions in eukaryotes.
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
Patrick M
PM
Lombardi
Heather D
HD
Angell
Douglas A
DA
Whittington
Erin F
EF
Flynn
Kanagalaghatta R
KR
Rajashankar
David W
DW
Christianson
D000619:Aminohydrolases / Q000737:chemistry* / Q000378:metabolism; D001419:Bacteria / Q000201:enzymology* / Q000378:metabolism; D002384:Catalysis; D019281:Dimerization; D056890:Eukaryota; D019143:Evolution, Molecular; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D011073:Polyamines / Q000378:metabolism*; D000581:Amidohydrolases
D000619:Aminohydrolases; D006655:Histone Deacetylases; D008024:Ligands; D011073:Polyamines; C058087:acetylpolyamine amidohydrolase; D000581:Amidohydrolases
J Bacteriol. 1996 Oct;178(19):5781-6
8824626
Biochem Biophys Res Commun. 1975 Jan 2;64(3):897-904
1096886
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21
20057044
J Biol Chem. 2002 Feb 1;277(5):3350-6
11726666
J Mol Biol. 2004 Apr 16;338(1):17-31
15050820
Biochemistry. 1981 Nov 24;20(24):6912-20
7317361
Methods Enzymol. 1997;276:594-611
9048382
Nucleic Acids Res. 2010 Jan;38(2):353-9
19920120
Curr Protoc Mol Biol. 2001 Nov;Chapter 2:Unit 2.4
18265184
Biochem Soc Trans. 2003 Apr;31(2):366-70
12653640
Nature. 1996 Oct 10;383(6600):554-7
8849731
Nat Protoc. 2006;1(5):2498-505
17406497
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):22-5
20057045
Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
15299374
Nat Rev Cancer. 2004 Oct;4(10):781-92
15510159
Nat Protoc. 2007;2(11):2728-33
18007608
Nucleic Acids Res. 2002 Mar 1;30(5):1114-23
11861901
J Am Chem Soc. 2010 Jul 14;132(27):9471-9
20568751
Arch Biochem Biophys. 1978 Jul;189(1):20-7
708044
Structure. 2004 Jul;12(7):1325-34
15242608
Methods Enzymol. 1997;276:307-26
27754618
Nat Rev Drug Discov. 2007 May;6(5):373-90
17464296
Nature. 1999 Sep 9;401(6749):188-93
10490031
Biochem Pharmacol. 1999 May 15;57(10):1095-103
11230796
Nucleic Acids Res. 1997 Sep 15;25(18):3693-7
9278492
Clin Cancer Res. 2009 Oct 1;15(19):5956-61
19789308
J Biol Chem. 2008 Sep 26;283(39):26694-704
18614528
Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4868-73
10220385
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
20383002
Clin Chem. 1974 Apr;20(4):470-5
4818200
Biochem Biophys Res Commun. 1988 Dec 30;157(3):1169-74
3207420
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
20124702
J Mol Biol. 2005 Nov 18;354(1):107-20
16242151
J Biol Chem. 2008 Apr 25;283(17):11355-63
18285338
J Biochem. 2006 Jan;139(1):11-6
16428314
J Biol Chem. 2002 Jan 4;277(1):187-93
11677242
J Biol Chem. 2010 Feb 26;285(9):6036-43
20029090
Arch Biochem Biophys. 1989 Aug 15;273(1):128-36
2757387
Arch Biochem Biophys. 1980 Aug;203(1):384-9
7406506