title: Enzymology of retinoic acid biosynthesis and degradation.
abstract: All-trans-retinoic acid is a biologically active derivative of vitamin A that regulates numerous physiological processes. The concentration of retinoic acid in the cells is tightly regulated, but the exact mechanisms responsible for this regulation are not completely understood, largely because the enzymes involved in the biosynthesis of retinoic acid have not been fully defined. Recent studies using in vitro and in vivo models suggest that several members of the short-chain dehydrogenase/reductase superfamily of proteins are essential for retinoic acid biosynthesis and the maintenance of retinoic acid homeostasis. However, the exact roles of some of these recently identified enzymes are yet to be characterized. The properties of the known contributors to retinoid metabolism have now been better defined and allow for more detailed understanding of their interactions with retinoid-binding proteins and other retinoid enzymes. At the same time, further studies are needed to clarify the interactions between the cytoplasmic and membrane-bound proteins involved in the processing of hydrophobic retinoid metabolites. This review summarizes current knowledge about the roles of various biosynthetic and catabolic enzymes in the regulation of retinoic acid homeostasis and outlines the remaining questions in the field.
authors: Department of Biochemistry and Molecular Genetics, Schools of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA. nkedishvili@uab.edu
authors: Natalia Y
authors: NY
authors: Kedishvili
mesh_terms: D004798:Enzymes / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D004798:Enzymes; D014212:Tretinoin
keywords: dehydrogenase; reductase; retinol; vitamin A
references: J Cell Physiol. 2011 Feb;226(2):322-30
references: 20836077
references: Chem Biol Interact. 2009 Mar 16;178(1-3):182-7
references: 18926804
references: Development. 2012 Jun;139(12):2150-5
references: 22619388
references: J Biol Chem. 2011 Feb 25;286(8):6542-53
references: 21138835
references: Biol Reprod. 1998 Apr;58(4):963-70
references: 9546726
references: Mol Cell Endocrinol. 1997 May 16;129(2):169-79
references: 9202400
references: Biochim Biophys Acta. 2009 Dec;1790(12):1660-4
references: 19766701
references: J Biol Chem. 2000 Dec 22;275(51):40106-12
references: 11007799
references: EMBO J. 2006 Jul 12;25(13):3203-13
references: 16763553
references: Biochem Pharmacol. 2012 Jan 1;83(1):149-63
references: 22020119
references: Genes Dev. 2007 May 1;21(9):1113-24
references: 17473173
references: Endocrinology. 1996 Nov;137(11):5028-35
references: 8895377
references: J Biol Chem. 2013 Jan 11;288(2):1250-65
references: 23105095
references: Arch Biochem Biophys. 2001 Feb 1;386(1):1-10
references: 11360992
references: Gastroenterology. 2001 Jan;120(1):179-89
references: 11208727
references: J Biol Chem. 2011 Aug 12;286(32):28343-56
references: 21659514
references: Physiol Genomics. 2011 Jan 7;43(1):57-67
references: 21045116
references: Steroids. 2001 Nov;66(11):845-8
references: 11576624
references: Biochem Pharmacol. 2000 Aug 15;60(4):517-26
references: 10874126
references: Biochemistry. 1995 May 30;34(21):7027-37
references: 7766612
references: Arch Biochem Biophys. 1993 Feb 1;300(2):751-5
references: 8382035
references: J Biol Chem. 1986 Oct 15;261(29):13592-7
references: 3759984
references: J Biol Chem. 2003 Aug 22;278(34):32380-9
references: 12807874
references: Biochemistry. 1990 Apr 24;29(16):3888-92
references: 2354160
references: J Biol Chem. 1997 Jun 20;272(25):15959-66
references: 9188497
references: Cell Mol Life Sci. 2008 Dec;65(24):3936-49
references: 19011747
references: J Biol Chem. 2001 Aug 24;276(34):32160-8
references: 11418584
references: Genesis. 2012 May;50(5):415-23
references: 22162152
references: J Histochem Cytochem. 1998 Oct;46(10):1103-11
references: 9742066
references: J Biol Chem. 1991 Feb 25;266(6):3622-9
references: 1995621
references: Dev Cell. 2004 Mar;6(3):411-22
references: 15030763
references: FASEB J. 2007 Sep;21(11):2886-96
references: 17435174
references: Int J Dev Biol. 2010;54(8-9):1267-75
references: 20563989
references: FASEB J. 2011 May;25(5):1641-52
references: 21285397
references: Cell Cycle. 2010 Jun 1;9(11):2177-88
references: 20543567
references: Nutrients. 2011 Jan;3(1):63-103
references: 21350678
references: Nat Rev Neurosci. 2007 Oct;8(10):755-65
references: 17882253
references: Am J Hum Genet. 2004 Oct;75(4):639-46
references: 15322982
references: J Biol Chem. 2011 Apr 15;286(15):13550-60
references: 21345790
references: J Biol Chem. 2013 Jan 4;288(1):589-97
references: 23155051
references: J Biol Chem. 1999 Apr 2;274(14):9556-63
references: 10092641
references: Mol Vis. 2012;18:2229-40
references: 22933835
references: J Nutr. 1997 Feb;127(2):218-24
references: 9039821
references: J Biol Chem. 1995 Jan 20;270(3):1107-12
references: 7836368
references: J Biol Chem. 2001 Jun 29;276(26):24194-202
references: 11304534
references: Nutrients. 2011 Apr;3(4):385-428
references: 22254103
references: Annu Rev Nutr. 2011 Aug 21;31:65-87
references: 21529158
references: Mol Cell. 2005 Apr 29;18(3):343-53
references: 15866176
references: Biochem J. 1969 Dec;115(4):609-19
references: 4391039
references: Cell Mol Life Sci. 2008 Dec;65(24):3895-906
references: 19011750
references: FEBS Lett. 2002 Nov 20;531(3):489-93
references: 12435598
references: Adv Exp Med Biol. 1994;352:187-200
references: 7832047
references: J Biol Chem. 2012 Mar 16;287(12):9061-71
references: 22291023
references: Annu Rev Pharmacol Toxicol. 2006;46:451-80
references: 16402912
references: J Lipid Res. 2010 Jul;51(7):1781-92
references: 20147703
references: Clin Cancer Res. 2005 Mar 1;11(5):1776-85
references: 15755999
references: Toxicology. 2004 Oct 15;203(1-3):41-8
references: 15363580
references: Hum Mol Genet. 2013 Feb 15;22(4):696-703
references: 23161670
references: J Biol Chem. 2001 Nov 23;276(47):44083-90
references: 11562362
references: Mol Cell Biol. 2003 Jul;23(13):4637-48
references: 12808103
references: Arch Biochem Biophys. 2007 Aug 15;464(2):241-50
references: 17537398
references: J Biol Chem. 2003 Mar 14;278(11):9856-61
references: 12519776
references: Biochim Biophys Acta. 2012 Jan;1821(1):152-67
references: 21621639
references: Lancet. 2003 Apr 19;361(9366):1336-43
references: 12711469
references: J Biol Chem. 2002 Aug 9;277(32):28909-15
references: 12036956
references: Mol Cell Endocrinol. 2001 Jan 22;171(1-2):111-7
references: 11165019
references: Int J Obes Relat Metab Disord. 1999 Jan;23(1):1-6
references: 10094571
references: Gene. 1997 Jun 3;191(2):167-72
references: 9218716
references: Arch Biochem Biophys. 1995 Aug 20;321(2):434-41
references: 7646070
references: Acta Biochim Pol. 2007;54(1):213-8
references: 17311113
references: J Biol Chem. 2012 Jul 13;287(29):24662-70
references: 22621924
references: Dev Biol. 2011 Sep 15;357(2):347-55
references: 21782811
references: Endocrinology. 2007 May;148(5):2148-56
references: 17289849
references: J Biol Chem. 2001 Apr 27;276(17):14110-6
references: 11278918
references: Gene Expr Patterns. 2008 Jul;8(6):438-442
references: 18502188
references: Biochem Biophys Res Commun. 1998 Aug 19;249(2):467-74
references: 9712720
references: Nat Genet. 2004 Aug;36(8):850-4
references: 15258582
references: Biochem J. 2006 Oct 1;399(1):101-9
references: 16787387
references: Am J Clin Nutr. 2012 Nov;96(5):1234S-44S
references: 23053549
references: J Lipid Res. 2000 Dec;41(12):2024-34
references: 11108736
references: J Biol Chem. 2001 Mar 2;276(9):6560-5
references: 11092891
references: Nucl Recept Signal. 2009;7:e002
references: 19381305
references: Endocrinology. 2000 May;141(5):1608-17
references: 10803568
references: Front Pharmacol. 2012 Apr 17;3:58
references: 22529810
references: J Biol Chem. 2002 Nov 1;277(44):41970-7
references: 12177003
references: J Biol Chem. 2013 Mar 29;288(13):9017-27
references: 23393141
references: J Biol Chem. 2007 Aug 31;282(35):25668-76
references: 17567582
references: J Biol Chem. 1999 Aug 20;274(34):23695-8
references: 10446126
references: Eur J Biochem. 1998 Oct 15;257(2):344-50
references: 9826179
references: Biochem J. 2000 Oct 1;351(Pt 1):67-77
references: 10998348
references: Annu Rev Nutr. 2010 Aug 21;30:201-17
references: 20415582
references: Invest Ophthalmol Vis Sci. 2002 Nov;43(11):3365-72
references: 12407145
references: Nutr Cancer. 1998;30(1):53-8
references: 9507513
references: J Biol Chem. 1998 Aug 21;273(34):21790-9
references: 9705317
references: Cancer Res. 2011 Jun 15;71(12):4161-71
references: 21507934
references: J Clin Invest. 2006 Jul;116(7):1767-75
references: 16823474
references: J Biol Chem. 2004 Jan 30;279(5):3434-8
references: 14623888
references: Drug Metab Dispos. 2000 Sep;28(9):1051-7
references: 10950848
references: Mol Cell Endocrinol. 2001 Jan 22;171(1-2):103-9
references: 11165018
references: J Cell Biol. 1991 Mar;112(5):965-79
references: 1847931
references: Cell. 2007 May 18;129(4):723-33
references: 17512406
references: FEBS Lett. 2000 Dec 29;487(2):282-6
references: 11150525
references: Biochim Biophys Acta. 2012 Jul;1820(7):859-69
references: 22498138
references: J Biol Chem. 2007 Dec 7;282(49):35621-8
references: 17925390
references: Biochem J. 2001 Mar 15;354(Pt 3):521-9
references: 11237856
references: Methods Enzymol. 1993;214:21-32
references: 8469142
references: Vitam Horm. 2007;75:197-222
references: 17368317
references: Nat Genet. 1999 Apr;21(4):444-8
references: 10192400
references: Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:129-52
references: 12432914
references: J Neurochem. 1968 Jul;15(7):643-57
references: 4386358
references: J Steroid Biochem Mol Biol. 2007 May;104(3-5):190-4
references: 17512723
references: Biol Reprod. 1997 Jan;56(1):125-32
references: 9002641
references: Development. 1995 Feb;121(2):539-48
references: 7768191
references: Biochemistry. 2003 Dec 23;42(50):14838-45
references: 14674758
references: Biochim Biophys Acta. 2012 Jan;1821(1):70-7
references: 21718801
references: Dev Biol. 2007 Feb 15;302(2):399-411
references: 17067568
references: Invest Ophthalmol Vis Sci. 2005 Oct;46(10):3562-9
references: 16186334
references: J Biol Chem. 2008 Jul 18;283(29):20299-308
references: 18502750
references: J Histochem Cytochem. 2005 Nov;53(11):1403-12
references: 15983114
references: Biochem Biophys Res Commun. 2010 Sep 17;400(2):207-11
references: 20709019
references: Cancer Res. 2002 Feb 15;62(4):1196-204
references: 11861404
references: J Steroid Biochem Mol Biol. 2011 May;125(1-2):46-56
references: 21272640
references: Mol Vis. 2012;18:1021-30
references: 22605914
references: Vitam Horm. 2007;75:69-95
references: 17368312
references: Chem Biol Interact. 2009 Mar 16;178(1-3):94-8
references: 19027726
references: Mol Pharmacol. 2000 Dec;58(6):1341-8
references: 11093772
references: Biochem Biophys Res Commun. 2000 May 10;271(2):334-6
references: 10799297
references: FEBS J. 2008 Jan;275(1):138-47
references: 18039331
references: J Nutr. 2000 Apr;130(4):728-32
references: 10736321
references: J Biol Chem. 1993 Oct 15;268(29):21545-52
references: 8408005
references: J Lipid Res. 2010 Feb;51(2):378-87
references: 19700416
references: Expert Opin Drug Metab Toxicol. 2009 Aug;5(8):875-86
references: 19519282
references: Expert Opin Drug Metab Toxicol. 2008 Jun;4(6):697-720
references: 18611112
references: J Biol Chem. 2006 Dec 8;281(49):37697-704
references: 17032653
references: Endocrinology. 1995 Jun;136(6):2730-40
references: 7750498
references: Biochem Pharmacol. 2010 Sep 15;80(6):903-12
references: 20513361
references: Front Biosci. 2006 Sep 01;11:2767-73
references: 16720349
references: Genomics. 2001 Mar 1;72(2):193-202
references: 11401432
references: Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16687-92
references: 21930923
references: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14036-41
references: 14623956
references: J Biol Chem. 1994 Apr 8;269(14):10538-44
references: 8144640
references: J Biol Chem. 1988 Nov 25;263(33):17715-23
references: 3053716
references: Biochim Biophys Acta. 2002 Apr 1;1596(1):156-62
references: 11983430
references: Endocrinology. 1996 Jul;137(7):3111-22
references: 8770937
references: Arch Ophthalmol. 2008 Sep;126(9):1301-7
references: 18779497
references: Dev Biol. 2010 Feb 1;338(1):1-14
references: 19874812
references: Genes Dev. 2001 Jan 15;15(2):226-40
references: 11157778
references: FASEB J. 2005 May;19(7):845-7
references: 15731294
references: Am J Physiol Gastrointest Liver Physiol. 2012 Sep 1;303(5):G578-88
references: 22790594
references: Development. 2009 Feb;136(3):461-72
references: 19141675
references: J Biol Chem. 1987 Aug 5;262(22):10550-6
references: 3611082
references: Annu Rev Biochem. 1995;64:201-33
references: 7574480
references: Development. 2009 Jun;136(12):2091-100
references: 19465599
references: Biochem J. 2000 Jun 15;348 Pt 3:481-95
references: 10839978
references: J Biol Chem. 2005 Mar 11;280(10):8694-704
references: 15634683
references: J Biol Chem. 2001 Jun 22;276(25):22278-86
references: 11294878
references: Mol Cell Biol. 2007 Feb;27(4):1370-9
references: 17130236
references: J Biol Chem. 2001 Jan 12;276(2):1353-60
references: 11022035
references: J Biol Chem. 2003 Sep 19;278(38):36085-90
references: 12851412
references: J Nutr. 2004 Jan;134(1):269S-275S
references: 14704332
references: Arch Biochem Biophys. 1984 Oct;234(1):305-12
references: 6486823
references: Mol Endocrinol. 2006 Feb;20(2):444-58
references: 16179381
references: Biochim Biophys Acta. 2009 Oct;1790(10):1266-73
references: 19520149
references: Nat Genet. 1999 Jun;22(2):188-91
references: 10369264
references: Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3710-5
references: 11274389
references: Proc Natl Acad Sci U S A. 2012 Aug 21;109(34):13668-73
references: 22869719
references: Biochem Pharmacol. 1999 Oct 1;58(7):1201-8
references: 10484078
references: Biochem Pharmacol. 2003 May 15;65(10):1685-90
references: 12754104
references: Cancer Biol Ther. 2007 Feb;6(2):238-44
references: 17218779
references: Invest Ophthalmol Vis Sci. 2000 Feb;41(2):337-48
references: 10670460
references: Genomics. 2006 Dec;88(6):820-830
references: 16860536
references: Birth Defects Res A Clin Mol Teratol. 2010 Oct;88(10):883-94
references: 20842651
references: Mech Dev. 1997 May;63(2):173-86
references: 9203140
references: Biochem J. 1999 Feb 15;338 ( Pt 1):23-7
references: 9931293
references: Mol Pharmacol. 2006 Jun;69(6):2007-14
references: 16551781
references: Biochemistry. 2003 Jan 28;42(3):776-84
references: 12534290
references: EMBO J. 1999 Sep 15;18(18):4903-14
references: 10487743
references: Biochemistry. 2005 May 10;44(18):7035-47
references: 15865448
references: J Biol Chem. 1998 Jul 31;273(31):19778-85
references: 9677409