title: A new member of the 4-methylideneimidazole-5-one-containing aminomutase family from the enediyne kedarcidin biosynthetic pathway.
abstract: 4-Methylideneimidazole-5-one (MIO)-containing aminomutases catalyze the conversion of L-α-amino acids to β-amino acids with either an (R) or an (S) configuration. L-phenylalanine and L-tyrosine are the only two natural substrates identified to date. The enediyne chromophore of the chromoprotein antitumor antibiotic kedarcidin (KED) harbors an (R)-2-aza-3-chloro-β-tyrosine moiety reminiscent of the (S)-3-chloro-5-hydroxy-β-tyrosine moiety of the C-1027 enediyne chromophore, the biosynthesis of which uncovered the first known MIO-containing aminomutase, SgcC4. Comparative analysis of the KED and C-1027 biosynthetic gene clusters inspired the proposal for (R)-2-aza-3-chloro-β-tyrosine biosynthesis starting from 2-aza-L-tyrosine, featuring KedY4 as a putative MIO-containing aminomutase. Here we report the biochemical characterization of KedY4, confirming its proposed role in KED biosynthesis. KedY4 is an MIO-containing aminomutase that stereospecifically catalyzes the conversion of 2-aza-L-tyrosine to (R)-2-aza-β-tyrosine, exhibiting no detectable activity toward 2-aza-L-phenylalanine or L-tyrosine as an alternative substrate. In contrast, SgcC4, which stereospecifically catalyzes the conversion of L-tyrosine to (S)-β-tyrosine in C-1027 biosynthesis, exhibits minimal activity with 2-aza-L-tyrosine as an alternative substrate but generating (S)-2-aza-β-tyrosine, a product with the opposite stereochemistry of KedY4. This report of KedY4 broadens the scope of known substrates for the MIO-containing aminomutase family, and comparative studies of KedY4 and SgcC4 provide an outstanding opportunity to examine how MIO-containing aminomutases control substrate specificity and product enantioselectivity.
authors: Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors: Sheng-Xiong
authors: SX
authors: Huang
authors: Jeremy R
authors: JR
authors: Lohman
authors: Tingting
authors: T
authors: Huang
authors: Ben
authors: B
authors: Shen
mesh_terms: D000641:Ammonia / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology; D019295:Computational Biology; D003516:Cycloparaffins / Q000737:chemistry*; D053281:Enediynes / Q000737:chemistry*; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism; D019751:Intramolecular Transferases / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008190:Lyases / Q000737:chemistry; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000737:chemistry*; D010649:Phenylalanine / Q000737:chemistry; D013302:Streptomyces / Q000378:metabolism; D013379:Substrate Specificity; D014443:Tyrosine / Q000737:chemistry
chemical_list: C479280:4-methylideneimidazole-5-one; D000970:Antineoplastic Agents; D003516:Cycloparaffins; D053281:Enediynes; D007093:Imidazoles; D009281:Naphthalenes; C080542:kedarcidin chromophore; D014443:Tyrosine; D010649:Phenylalanine; D000641:Ammonia; D008190:Lyases; D019751:Intramolecular Transferases
keywords: Streptoalloteichus sp.; Streptomyces globisporus; amonia lyase; enzyme; natural product
references: J Am Chem Soc. 2007 Dec 26;129(51):15744-5
references: 18052279
references: Chembiochem. 2009 Mar 2;10(4):741-50
references: 19222035
references: Angew Chem Int Ed Engl. 2012 Mar 19;51(12):2898-902
references: 22319000
references: Curr Opin Chem Biol. 2009 Oct;13(4):460-8
references: 19620019
references: Biochemistry. 2011 Nov 22;50(46):10082-90
references: 21985059
references: Mol Biosyst. 2013 Mar;9(3):478-91
references: 23360970
references: Annu Rev Biochem. 2001;70:121-48
references: 11395404
references: Chem Pharm Bull (Tokyo). 1975 Nov;23(11):2669-77
references: 1218439
references: J Biol Chem. 2004 Dec 24;279(52):53947-54
references: 15494399
references: J Biol Chem. 2007 Jul 27;282(30):21810-7
references: 17545150
references: Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4183-8
references: 19246381
references: Angew Chem Int Ed Engl. 2012 Apr 27;51(18):4344-8
references: 22461423
references: Science. 2002 Aug 16;297(5584):1170-3
references: 12183628
references: Bioorg Med Chem Lett. 2008 May 15;18(10):3099-102
references: 18078753
references: J Am Chem Soc. 2006 Aug 23;128(33):10660-1
references: 16910643
references: Chem Rev. 2011 Apr 13;111(4):2487-506
references: 21370834
references: Biopolymers. 2010 Sep;93(9):802-10
references: 20577998
references: Methods Enzymol. 2012;516:321-43
references: 23034236
references: Curr Opin Chem Biol. 2011 Apr;15(2):234-40
references: 21131229
references: Org Lett. 2012 May 4;14(9):2300-3
references: 22519717
references: J Biol Chem. 2006 Oct 6;281(40):29633-40
references: 16887797
references: Biochemistry. 2011 Apr 12;50(14):2919-30
references: 21361343
references: J Am Chem Soc. 2005 Aug 24;127(33):11594-5
references: 16104723
references: J Am Chem Soc. 2011 Jun 8;133(22):8531-3
references: 21561099
references: J Am Chem Soc. 2007 May 2;129(17):5381-3
references: 17417855
references: J Am Chem Soc. 2007 Oct 31;129(43):13082-94
references: 17918933
references: J Am Chem Soc. 2007 Oct 17;129(41):12432-8
references: 17887753
references: J Am Chem Soc. 2003 May 21;125(20):6062-3
references: 12785829
references: Methods Enzymol. 2012;516:299-319
references: 23034235
references: Biochemistry. 2003 Nov 4;42(43):12708-18
references: 14580219
references: Biochemistry. 2007 Jun 19;46(24):7205-14
references: 17516659