Vitamin A (retinol) can be metabolised into active retinoid metabolites that function either as a chromophore in vision or in regulating gene expression transcriptionally and post-transcriptionally. Genes regulated by retinoids are essential for reproduction, embryonic development, growth, and multiple processes in the adult, including energy balance, neurogenesis, and the immune response. The retinoid used as a cofactor in the visual cycle is 11-cis-retinal (11cRAL). The non-visual cycle effects of retinol are mediated by retinoic acid (RA), generated by two-step conversion from retinol (Napoli 2012). All-trans-retinoic acid (atRA) is the major activated metabolite of retinol. An isomer, 9-cis-retinoic acid (9cRA) has biological activity, but has not been detected in vivo, except in the pancreas. An alternative route involves BCO1 cleavage of carotenoids into retinal, which is then reduced into retinol in the intestine (Harrison 2012). The two isomers of RA serve as ligands for retinoic acid receptors (RAR) that regulate gene expression. (Das et al. 2014). RA is catabolised to oxidised metabolites such as 4-hydroxy-, 18-hydroxy- or 4-oxo-RA by CYP family enzymes, these metabolites then becoming substrates for Phase II conjugation enzymes (Ross & Zolfaghari 2011).
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Amengual J, Petrov P, Bonet ML, Ribot J, Palou A.; ''Induction of carnitine palmitoyl transferase 1 and fatty acid oxidation by retinoic acid in HepG2 cells.''; PubMedEurope PMCScholia
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Belyaeva OV, Korkina OV, Stetsenko AV, Kedishvili NY.; ''Human retinol dehydrogenase 13 (RDH13) is a mitochondrial short-chain dehydrogenase/reductase with a retinaldehyde reductase activity.''; PubMedEurope PMCScholia
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Ross AC, Zolfaghari R.; ''Cytochrome P450s in the regulation of cellular retinoic acid metabolism.''; PubMedEurope PMCScholia
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Zhu H, Shi J, de Vries Y, Arvidson DN, Cregg JM, Woldegiorgis G.; ''Functional studies of yeast-expressed human heart muscle carnitine palmitoyltransferase I.''; PubMedEurope PMCScholia
Harris RA, Bowker-Kinley MM, Wu P, Jeng J, Popov KM.; ''Dihydrolipoamide dehydrogenase-binding protein of the human pyruvate dehydrogenase complex. DNA-derived amino acid sequence, expression, and reconstitution of the pyruvate dehydrogenase complex.''; PubMedEurope PMCScholia
Hohoff C, Börchers T, Rüstow B, Spener F, van Tilbeurgh H.; ''Expression, purification, and crystal structure determination of recombinant human epidermal-type fatty acid binding protein.''; PubMedEurope PMCScholia
Sessler RJ, Noy N.; ''A ligand-activated nuclear localization signal in cellular retinoic acid binding protein-II.''; PubMedEurope PMCScholia
Kedishvili NY, Chumakova OV, Chetyrkin SV, Belyaeva OV, Lapshina EA, Lin DW, Matsumura M, Nelson PS.; ''Evidence that the human gene for prostate short-chain dehydrogenase/reductase (PSDR1) encodes a novel retinal reductase (RalR1).''; PubMedEurope PMCScholia
Inoue K, Nishimukai H, Yamasawa K.; ''Purification and partial characterization of aldehyde dehydrogenase from human erythrocytes.''; PubMedEurope PMCScholia
Xie P, Parsons SH, Speckhard DC, Bosron WF, Hurley TD.; ''X-ray structure of human class IV sigmasigma alcohol dehydrogenase. Structural basis for substrate specificity.''; PubMedEurope PMCScholia
Gudi R, Bowker-Kinley MM, Kedishvili NY, Zhao Y, Popov KM.; ''Diversity of the pyruvate dehydrogenase kinase gene family in humans.''; PubMedEurope PMCScholia
Kolobova E, Tuganova A, Boulatnikov I, Popov KM.; ''Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites.''; PubMedEurope PMCScholia
Taimi M, Helvig C, Wisniewski J, Ramshaw H, White J, Amad M, Korczak B, Petkovich M.; ''A novel human cytochrome P450, CYP26C1, involved in metabolism of 9-cis and all-trans isomers of retinoic acid.''; PubMedEurope PMCScholia
Morillas M, López-Viñas E, Valencia A, Serra D, Gómez-Puertas P, Hegardt FG, Asins G.; ''Structural model of carnitine palmitoyltransferase I based on the carnitine acetyltransferase crystal.''; PubMedEurope PMCScholia
Gobin S, Thuillier L, Jogl G, Faye A, Tong L, Chi M, Bonnefont JP, Girard J, Prip-Buus C.; ''Functional and structural basis of carnitine palmitoyltransferase 1A deficiency.''; PubMedEurope PMCScholia
Morillas M, Gómez-Puertas P, Rubí B, Clotet J, Ariño J, Valencia A, Hegardt FG, Serra D, Asins G.; ''Structural model of a malonyl-CoA-binding site of carnitine octanoyltransferase and carnitine palmitoyltransferase I: mutational analysis of a malonyl-CoA affinity domain.''; PubMedEurope PMCScholia
Haeseleer F, Huang J, Lebioda L, Saari JC, Palczewski K.; ''Molecular characterization of a novel short-chain dehydrogenase/reductase that reduces all-trans-retinal.''; PubMedEurope PMCScholia
Napoli JL.; ''Physiological insights into all-trans-retinoic acid biosynthesis.''; PubMedEurope PMCScholia
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Laue K, Pogoda HM, Daniel PB, van Haeringen A, Alanay Y, von Ameln S, Rachwalski M, Morgan T, Gray MJ, Breuning MH, Sawyer GM, Sutherland-Smith AJ, Nikkels PG, Kubisch C, Bloch W, Wollnik B, Hammerschmidt M, Robertson SP.; ''Craniosynostosis and multiple skeletal anomalies in humans and zebrafish result from a defect in the localized degradation of retinoic acid.''; PubMedEurope PMCScholia
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von Bahr-Lindström H, Höög JO, Hedén LO, Kaiser R, Fleetwood L, Larsson K, Lake M, Holmquist B, Holmgren A, Hempel J.; ''cDNA and protein structure for the alpha subunit of human liver alcohol dehydrogenase.''; PubMedEurope PMCScholia
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Noy N.; ''Retinoid-binding proteins: mediators of retinoid action.''; PubMedEurope PMCScholia
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Brown RM, Head RA, Brown GK.; ''Pyruvate dehydrogenase E3 binding protein deficiency.''; PubMedEurope PMCScholia
Noy N.; ''The one-two punch: Retinoic acid suppresses obesity both by promoting energy expenditure and by inhibiting adipogenesis.''; PubMedEurope PMCScholia
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Phase II of biotransformation is concerned with conjugation, that is using groups from cofactors to react with functional groups present or introduced from phase I on the compound. The enzymes involved are a set of transferases which perform the transfer of the cofactor group to the substrate. The resultant conjugation results in greatly increasing the excretory potential of compounds. Although most conjugations result in pharmacological inactivation or detoxification, some can result in bioactivation. Most of the phase II enzymes are located in the cytosol except UDP-glucuronosyltransferases (UGT), which are microsomal. Phase II reactions are typically much faster than phase I reactions therefore the rate-limiting step for biotransformation of a compound is usually the phase I reaction. Phase II metabolism can deal with all the products of phase I metabolism, be they reactive (Type I substrate) or unreactive/poorly active (Type II substrate) compounds. With the exception of glutathione, the conjugating species needs to be made chemically reactive after synthesis. The availability of the cofactor in the synthesis may be a rate-limiting factor in some phase II pathways as it may prevent the formation of enough conjugating species to deal with the substrate or it's metabolite. As many substrates and/or their metabolites are chemically reactive, their continued presence may lead to toxicity.
Carnitine palmitoyl transferase 1 (CPT1) associated with the inner mitochondrial membrane, catalyzes the reaction of palmitoyl-CoA (PALM-CoA) from the cytosol with carnitine (CAR) in the mitochondrial intermembrane space to form palmitoylcarnitine (L-PCARN) and CoA-SH. Three CPT1 isoforms exist; CPT1A, B and C. In the body, CPT1A is most abundant in liver while CPT1B is abundant in muscle. CPT1C is mainly expressed in neurons and localises to the ER and not to the mitochondria. It has little or no enzymatic activity in fatty acid oxidation. Both CPT1A and CPT1B are inhibited by malonyl-CoA (Morillas et al. 2002, 2004; Zammit et al. 2001; Zhu et al. 1997). Mutations in CPT1A are associated with defects in fatty acid metabolism and fasting intoilerance, consistent with the role assigned to CPT1 from studies in vitro and in animal models (IJlst et al. 1998; Gobin et al. 2003). In the nucleus, cellular retinoic acid-binding protein 1 or 2 (CRABP1 or 2), bound to all-trans-retinoic acid (atRA), directly binds to the heterodimeric complex of retinoic acid receptor alpha RXRA) and peroxisome proliferator-activated receptor delta (PPARD). When bound to PPARD, atRA can significantly increase the expression of proteins involved in fatty acid oxidation such as CPT1A via its induction of PPARD (Amengual et al. 2012).
The mitochondrial pyruvate dehydrogenase (PDH) complex (lipo-PDH) irreversibly decarboxylates pyruvate to acetyl CoA, thereby serving to oxidatively remove lactate, which is in equilibrium with pyruvate, and to link glycolysis in the cytosol to the tricarboxylic acid cycle in the mitochondria matrix. Pyruvate Dehydrogenase Kinase (PDK) in the mitochondrial matrix catalyzes the phosphorylation of serine residues of the E1 alpha subunit of the PDH complex, inactivating it. Pyruvate negatively regulates this reaction, and NADH and acetyl CoA positively regulate it (Bao et al. 2004). Four PDK isoforms have been identified and shown to catalyze the phosphorylation of E1 alpha in vitro (Gudi et al. 1995, Kolobova et al. 2001, Rowles et al. 1996). They differ in their expression patterns and quantitative responses to regulatory small molecules. All four isoforms catalyze the phosphorylation of serine residues 293 ("site 1") and 300 ("site 2"); PDK1 can also catalyse the phosphorylation of serine 232 ("site 3"). Phosphorylation of a single site in a single E1 alpha subunit is sufficient for enzyme inactivation (Bowker-Kinley et al. 1998, Gudi et al. 1995, Kolobova et al. 2001, Korotchkina and Patel, 2001).
Endogenous retinoic acids (RA) which play a role in gene regulation exist as either cis or trans isomers. While CYP26C1 can also hydroxylate the trans form, it is unique in 4-hydroxylating the 9-cis isomer of RA (9cRA) in vitro (Taimi et al. 2004). However, the importance of 9cRA as an endogenous retinoid outside of the pancreas has not been demonstrated.
Cellular retinoic acid-binding protein 2 (CRABP2) is a cytosolic, lipid-binding protein thought to bind its natural ligand, all-trans-retinoic acid (atRA) and mediate its delivery to retinoic acid receptors (RARs) within the nucleus (Kleywegt et al. 1994). CRABP2 forms a beta-barrel structure within which a hydrophobic ligand can be accommodated. Once atRA binds to CRABP2, the resulting complex translocates to the nucleus (Budhu & Noy 2002). A ligand activated nuclear-localisation signal appears to be critical for nuclear localisation (Sessler & Noy 2005). Sumoylation of CRABPs is also essential for atRA-induced dissociation of CRABPs from the ER membrane. For CRABP2, the site K102 is sumoylated (Majumdar et al. 2011).
In the nucleus, cellular retinoic acid binding protein 2 (CRABP2), bound to all trans retinoic acid (atRA), directly binds to heterodimeric nuclear retinoic acid receptors (RAR:RXR) to form a complex through which atRA is channeled from the binding protein to RAR (Majumdar et al. 2011). The RAR:RXR heterodimer can be formed between any of three receptor isoforms for each; RARA, RARB, or RARG with RXRA, RXRB, or RXRG (Neiderreither and Dolle 2008). RARA requires sumoylation and phosphorylation for ligand binding and nuclear localisation (Zhu et al. 2009, Santos & Kim 2010).
RAR:RXR bind to their RA response elements (RARE, composed of tandem direct repeats of 5'-AGGTCA-3' spaced by either 2 bp or 5 bp (DR2, DR5) in response to their physiological ligand atRA, and regulate gene expression in various biological processes.
Multiple retinol dehydrogenases (RDH), members of the short-chain dehydrogenase/reductase (SDR) gene family, are candidates for catalysing conversion of retinol into retinal under physiological conditions (Napoli 2012). These include RDH16 (aka RoDH-4, RDH-E, Rdh1), RDH10, DHRS9 (aka retSDR8) and RDHE2. Two of these, Rdh1 (human ortholog RDH16) and Rdh10 (human ortholog RDH10), have been knocked out in mice and display RA-associated phenotypes. Both are membrane bound oxidoreductases that reversibly catalyse the first and rate limiting step in retinoic acid biosynthesis, and use NAD+ as cofactor to the corresponding aldehyde all trans retinal (atRAL) (Gough et al. 1998, Jurukovski et al. 1999, Pecozzi et al. 2003). The other RDH are currently under study, but have not been ablated in mice.
Several aldehyde dehydrogenases catalyse the irreversible oxidation of retinal to retinoic acid. ALDH1A1, 2 and 3 utilise NAD+ as cofactor to oxidise all-trans-retinal (atRAL) to all-trans-retinoic acid (atRA). They are cytosolic enzymes which are functional in their homotetrameric states (Yoshida et al. 1993, Duester 2008, Bchini et al. 2013).
All-trans-retinoic acid (atRA) is a biologically activated metabolite of vitamin A (retinol) and is essential for reproduction, embryonic development, growth, and multiple processes in the adult, including energy balance, neurogenesis, and the immune response. Cytochrome P450 26A1 and B1 (CYP26A1 and B1) play a key role in retinoid metabolism (Ross & Zolfaghari 2011). They 4-hydroxylate all-trans-retinoic acid (atRA), delivered by CRABP1, to form all-trans-4-hydroxyretinoic acid (4OH-atRA) which can then be eliminated from the body. CYP26A1 and B1 are also able to 4-hydroxylate 9-cis-retinoic acid and 13-cis-retinoic acid (9cRA and 13cRA respectively) in vitro. These enzymes are also produce 18-hydroxy and 4-oxo forms of these retinoic acids (not shown here).
The inactivation of RA by CYP26B1 is essential for postnatal survival and maintenance of the undifferentiated state of male germ cells during embryonic development in Sertoli cells. Excessive RA also has teratogenic effects in the limb and craniofacial skeleton. Defects in CYP26B1 can cause radiohumeral fusions with other skeletal and craniofacial anomalies (RHFCA; MIM:614416) (Laue et al. 2011).
Some alcohol dehydrogenases (ADHs) utilise NAD+ as cofactor to reversibly oxidise all-trans-retinol (atROL) to all-trans-retinal (atRAL), a retinoid aldehyde, in vitro (von Bahr-Lindstrom et al. 1986, Ikuta et al. 1986, von Bahr-Lindstrom et al. 1991, Xie et al. 1997). ADH1A (ADH1) and ADH4 have high activity and ADH1C (ADH3) has low activity with non-physiological amounts of retinol in vitro. ADH1A and ADH1C metabolize toxic amounts of retinol in vivo, but ADH4 does not. Physiological contributions of ADHs to retinol metabolism have not been demonstrated, in contrast to RDHs.
11-cis-retinol dehydrogenase (RDH5) and RDH11 catalyse the final step in the biosynthesis of 11-cis-retinal (11cRAL), the universal chromophore of visual pigments, whereas RDH8, RDH12, and DHRS3 (retSDR1) catalyze the conversion of all-trans-retinal (atRAL) into all-trans-retinol (atROL) to maintain the cycle (Parker & Crouch 2010). Defects in the RDH5 gene can cause fundus albipunctatus (RPA; MIM:136880), a rare form of stationary night blindness characterised by a delay in the regeneration of cone and rod photopigments (Yamamoto et al. 1999).
Multiple reductases may contribute to the reduction of all-trans-retinal (atRAL) to all-trans-retinol (atROL), including RDH11 (aka PSDR1, RalR1), RDH14, DHRS3 (aka retSDR1, RDH17) and DHRS4 (aka RRD, SCAD-SRL) (Haeseleer et al. 1998, Haeseleer et al. 2002, Kedishvili et al. 2002, Lin et al. 2001, Zhen et al. 2003, Belyaeva et al. 2008).
In the nucleus, all-trans-retinoic acid (atRA), bounds to epidermal fatty acid-binding protein (FABP5), is transferred to the heterodimeric complex of retinoic acid receptor alpha RXRA) and peroxisome proliferator-activated receptor delta (PPARD). When bound to PPARD, atRA can significantly increase the expression of proteins involved in fatty acid oxidation and energy metabolism via its induction of PPARD (Wolf 2010, Amengual et al. 2012, Noy 2013).
The cytosolic aldo-keto reductase 1C3 (AKR1C3) can reduce all-trans-retinal (atRAL) to all-trans-retinol (atROL) (Ruiz et al. 2011). AKR1C3 functions to reduce synthesis of atRA to prevent toxic or teratogenic effects of excess atRA.
Epidermal fatty acid-binding protein (FABP5) is a cytosolic, lipid-binding protein thought to bind all-trans-retinoic acid (atRA) and mediate its delivery to retinoic acid receptors (RARs) within the nucleus (Hohoff et al. 1999, Smathers & Petersen 2011).
All-trans-retinoic acid (atRA) metabolism can be mediated by CYP26 degradation. Cellular retinol-binding protein I (CRABP1) binds and delivers atRA to CY26 enzymes (Noy 2000).
Multiple reductases may contribute to the reduction of all-trans-retinal (atRAL) to all-trans-retinol (atROL). Human retinol dehydrogenase 13 (RDH13) is located on the outer surface of the mitochondrial inner membrane where it is thought to protect mitochondria against oxidative stress associated with the highly reactive retinaldehyde (Belyaeva et al. 2008).
Epidermal fatty acid-binding protein (FABP5) is a cytosolic, lipid-binding protein thought to bind all-trans-retinoic acid (atRA) and mediate its delivery to retinoic acid receptors (RARs) within the nucleus (Hohoff et al. 1999, Smathers & Petersen 2011).
In the nucleus, all-trans-retinoic acid (atRA), bounds to epidermal fatty acid-binding protein (FABP5), is transferred to the heterodimeric complex of retinoic acid receptor alpha RXRA) and peroxisome proliferator-activated receptor delta (PPARD). When bound to PPARD, atRA can significantly increase the expression of proteins involved in fatty acid oxidation and energy metabolism via its induction of PPARD (Wolf 2010, Amengual et al. 2012, Noy 2013).
In the nucleus, cellular retinoic acid binding protein 2 (CRABP2), bound to all trans retinoic acid (atRA), directly binds to heterodimeric nuclear retinoic acid receptors (RAR:RXR) to form a complex through which atRA is channeled from the binding protein to RAR (Majumdar et al. 2011). The RAR:RXR heterodimer can be formed between any of three receptor isoforms for each; RARA, RARB, or RARG with RXRA, RXRB, or RXRG (Neiderreither and Dolle 2008). RARA requires sumoylation and phosphorylation for ligand binding and nuclear localisation (Zhu et al. 2009, Santos & Kim 2010).
RAR:RXR bind to their RA response elements (RARE, composed of tandem direct repeats of 5'-AGGTCA-3' spaced by either 2 bp or 5 bp (DR2, DR5) in response to their physiological ligand atRA, and regulate gene expression in various biological processes.
Cellular retinoic acid-binding protein 2 (CRABP2) is a cytosolic, lipid-binding protein thought to bind its natural ligand, all-trans-retinoic acid (atRA) and mediate its delivery to retinoic acid receptors (RARs) within the nucleus (Kleywegt et al. 1994). CRABP2 forms a beta-barrel structure within which a hydrophobic ligand can be accommodated. Once atRA binds to CRABP2, the resulting complex translocates to the nucleus (Budhu & Noy 2002). A ligand activated nuclear-localisation signal appears to be critical for nuclear localisation (Sessler & Noy 2005). Sumoylation of CRABPs is also essential for atRA-induced dissociation of CRABPs from the ER membrane. For CRABP2, the site K102 is sumoylated (Majumdar et al. 2011).
Aldehyde dehydrogenase family 8 member A1 (ALDH8A1, ALDH12) can preferentially mediate the oxidation of 9-cis-retinal (9cRAL) into the retinoid X receptor ligand 9-cis-retinoic acid (9cRA) (Lin & Napoli 2000). ALDH8A1 might function in the pathway of 9-cis-retinal metabolism.
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Conjugation of
compoundsPhase II metabolism can deal with all the products of phase I metabolism, be they reactive (Type I substrate) or unreactive/poorly active (Type II substrate) compounds. With the exception of glutathione, the conjugating species needs to be made chemically reactive after synthesis. The availability of the cofactor in the synthesis may be a rate-limiting factor in some phase II pathways as it may prevent the formation of enough conjugating species to deal with the substrate or it's metabolite. As many substrates and/or their metabolites are chemically reactive, their continued presence may lead to toxicity.
Annotated Interactions
In the nucleus, cellular retinoic acid-binding protein 1 or 2 (CRABP1 or 2), bound to all-trans-retinoic acid (atRA), directly binds to the heterodimeric complex of retinoic acid receptor alpha RXRA) and peroxisome proliferator-activated receptor delta (PPARD). When bound to PPARD, atRA can significantly increase the expression of proteins involved in fatty acid oxidation such as CPT1A via its induction of PPARD (Amengual et al. 2012).
RAR:RXR bind to their RA response elements (RARE, composed of tandem direct repeats of 5'-AGGTCA-3' spaced by either 2 bp or 5 bp (DR2, DR5) in response to their physiological ligand atRA, and regulate gene expression in various biological processes.
The inactivation of RA by CYP26B1 is essential for postnatal survival and maintenance of the undifferentiated state of male germ cells during embryonic development in Sertoli cells. Excessive RA also has teratogenic effects in the limb and craniofacial skeleton. Defects in CYP26B1 can cause radiohumeral fusions with other skeletal and craniofacial anomalies (RHFCA; MIM:614416) (Laue et al. 2011).
RAR:RXR bind to their RA response elements (RARE, composed of tandem direct repeats of 5'-AGGTCA-3' spaced by either 2 bp or 5 bp (DR2, DR5) in response to their physiological ligand atRA, and regulate gene expression in various biological processes.