Fatty acyl-CoA biosynthesis involves following steps: -Palmitate synthesis catalyzed by Acetyl-CoA carboxylase and Fatty acid synthase -Conversion of palmitic acid to long chain fatty acids and -Conversion of long chain fatty acids to fatty acyl-CoA by acyl-CoA synthases.
View original pathway at:Reactome.
Ikeda M, Kanao Y, Yamanaka M, Sakuraba H, Mizutani Y, Igarashi Y, Kihara A.; ''Characterization of four mammalian 3-hydroxyacyl-CoA dehydratases involved in very long-chain fatty acid synthesis.''; PubMedEurope PMCScholia
Gnoni GV, Priore P, Geelen MJ, Siculella L.; ''The mitochondrial citrate carrier: metabolic role and regulation of its activity and expression.''; PubMedEurope PMCScholia
Wang J, Yu L, Schmidt RE, Su C, Huang X, Gould K, Cao G.; ''Characterization of HSCD5, a novel human stearoyl-CoA desaturase unique to primates.''; PubMedEurope PMCScholia
Autio KJ, Kastaniotis AJ, Pospiech H, Miinalainen IJ, Schonauer MS, Dieckmann CL, Hiltunen JK.; ''An ancient genetic link between vertebrate mitochondrial fatty acid synthesis and RNA processing.''; PubMedEurope PMCScholia
Fujimoto Y, Itabe H, Kinoshita T, Homma KJ, Onoduka J, Mori M, Yamaguchi S, Makita M, Higashi Y, Yamashita A, Takano T.; ''Involvement of ACSL in local synthesis of neutral lipids in cytoplasmic lipid droplets in human hepatocyte HuH7.''; PubMedEurope PMCScholia
Jayakumar A, Tai MH, Huang WY, al-Feel W, Hsu M, Abu-Elheiga L, Chirala SS, Wakil SJ.; ''Human fatty acid synthase: properties and molecular cloning.''; PubMedEurope PMCScholia
Grayson C, Molday RS.; ''Dominant negative mechanism underlies autosomal dominant Stargardt-like macular dystrophy linked to mutations in ELOVL4.''; PubMedEurope PMCScholia
Mikkelsen J, Witkowski A, Smith S.; ''Interaction of rat mammary gland thioesterase II with fatty acid synthetase is dependent on the presence of acyl chains on the synthetase.''; PubMedEurope PMCScholia
Elshourbagy NA, Near JC, Kmetz PJ, Wells TN, Groot PH, Saxty BA, Hughes SA, Franklin M, Gloger IS.; ''Cloning and expression of a human ATP-citrate lyase cDNA.''; PubMedEurope PMCScholia
Venkatesan R, Sah-Teli SK, Awoniyi LO, Jiang G, Prus P, Kastaniotis AJ, Hiltunen JK, Wierenga RK, Chen Z.; ''Insights into mitochondrial fatty acid synthesis from the structure of heterotetrameric 3-ketoacyl-ACP reductase/3R-hydroxyacyl-CoA dehydrogenase.''; PubMedEurope PMCScholia
Gassler N, Roth W, Funke B, Schneider A, Herzog F, Tischendorf JJ, Grund K, Penzel R, Bravo IG, Mariadason J, Ehemann V, Sykora J, Haas TL, Walczak H, Ganten T, Zentgraf H, Erb P, Alonso A, Autschbach F, Schirmacher P, Knüchel R, Kopitz J.; ''Regulation of enterocyte apoptosis by acyl-CoA synthetase 5 splicing.''; PubMedEurope PMCScholia
Yao H, Ye J.; ''Long chain acyl-CoA synthetase 3-mediated phosphatidylcholine synthesis is required for assembly of very low density lipoproteins in human hepatoma Huh7 cells.''; PubMedEurope PMCScholia
Abu-Elheiga L, Jayakumar A, Baldini A, Chirala SS, Wakil SJ.; ''Human acetyl-CoA carboxylase: characterization, molecular cloning, and evidence for two isoforms.''; PubMedEurope PMCScholia
Beld J, Lee DJ, Burkart MD.; ''Fatty acid biosynthesis revisited: structure elucidation and metabolic engineering.''; PubMedEurope PMCScholia
INSULL W, AHRENS EH.; ''The fatty acids of human milk from mothers on diets taken ad libitum.''; PubMedEurope PMCScholia
Watkins PA, Maiguel D, Jia Z, Pevsner J.; ''Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome.''; PubMedEurope PMCScholia
Naganuma T, Sato Y, Sassa T, Ohno Y, Kihara A.; ''Biochemical characterization of the very long-chain fatty acid elongase ELOVL7.''; PubMedEurope PMCScholia
Soyombo AA, Hofmann SL.; ''Molecular cloning and expression of palmitoyl-protein thioesterase 2 (PPT2), a homolog of lysosomal palmitoyl-protein thioesterase with a distinct substrate specificity.''; PubMedEurope PMCScholia
Pei Z, Oey NA, Zuidervaart MM, Jia Z, Li Y, Steinberg SJ, Smith KD, Watkins PA.; ''The acyl-CoA synthetase "bubblegum" (lipidosin): further characterization and role in neuronal fatty acid beta-oxidation..''; PubMedEurope PMCScholia
Agbaga MP, Brush RS, Mandal MN, Henry K, Elliott MH, Anderson RE.; ''Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids.''; PubMedEurope PMCScholia
Libertini LJ, Smith S.; ''Purification and properties of a thioesterase from lactating rat mammary gland which modifies the product specificity of fatty acid synthetase.''; PubMedEurope PMCScholia
Longo I, Frints SG, Fryns JP, Meloni I, Pescucci C, Ariani F, Borghgraef M, Raynaud M, Marynen P, Schwartz C, Renieri A, Froyen G.; ''A third MRX family (MRX68) is the result of mutation in the long chain fatty acid-CoA ligase 4 (FACL4) gene: proposal of a rapid enzymatic assay for screening mentally retarded patients.''; PubMedEurope PMCScholia
Moon YA, Horton JD.; ''Identification of two mammalian reductases involved in the two-carbon fatty acyl elongation cascade.''; PubMedEurope PMCScholia
Shimamura K, Takahashi H, Kitazawa H, Miyamoto Y, Nagumo A, Tang C, Dean D, Nagase T, Sato N, Tokita S.; ''Identification and characterization of a selective radioligand for ELOVL6.''; PubMedEurope PMCScholia
Pei Z, Fraisl P, Berger J, Jia Z, Forss-Petter S, Watkins PA.; ''Mouse very long-chain Acyl-CoA synthetase 3/fatty acid transport protein 3 catalyzes fatty acid activation but not fatty acid transport in MA-10 cells.''; PubMedEurope PMCScholia
Chen Z, Kastaniotis AJ, Miinalainen IJ, Rajaram V, Wierenga RK, Hiltunen JK.; ''17beta-hydroxysteroid dehydrogenase type 8 and carbonyl reductase type 4 assemble as a ketoacyl reductase of human mitochondrial FAS.''; PubMedEurope PMCScholia
Cohen DE.; ''New players on the metabolic stage: How do you like Them Acots?''; PubMedEurope PMCScholia
Zhang S, Yang Y, Shi Y.; ''Characterization of human SCD2, an oligomeric desaturase with improved stability and enzyme activity by cross-linking in intact cells.''; PubMedEurope PMCScholia
Geissler WM, Davis DL, Wu L, Bradshaw KD, Patel S, Mendonca BB, Elliston KO, Wilson JD, Russell DW, Andersson S.; ''Male pseudohermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid dehydrogenase 3.''; PubMedEurope PMCScholia
Meloni I, Muscettola M, Raynaud M, Longo I, Bruttini M, Moizard MP, Gomot M, Chelly J, des Portes V, Fryns JP, Ropers HH, Magi B, Bellan C, Volpi N, Yntema HG, Lewis SE, Schaffer JE, Renieri A.; ''FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation.''; PubMedEurope PMCScholia
Hunt MC, Siponen MI, Alexson SE.; ''The emerging role of acyl-CoA thioesterases and acyltransferases in regulating peroxisomal lipid metabolism.''; PubMedEurope PMCScholia
Smith S, Witkowski A, Joshi AK.; ''Structural and functional organization of the animal fatty acid synthase.''; PubMedEurope PMCScholia
Edvardson S, Porcelli V, Jalas C, Soiferman D, Kellner Y, Shaag A, Korman SH, Pierri CL, Scarcia P, Fraenkel ND, Segel R, Schechter A, Frumkin A, Pines O, Saada A, Palmieri L, Elpeleg O.; ''Agenesis of corpus callosum and optic nerve hypoplasia due to mutations in SLC25A1 encoding the mitochondrial citrate transporter.''; PubMedEurope PMCScholia
Ohno Y, Suto S, Yamanaka M, Mizutani Y, Mitsutake S, Igarashi Y, Sassa T, Kihara A.; ''ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.''; PubMedEurope PMCScholia
Tamura K, Makino A, Hullin-Matsuda F, Kobayashi T, Furihata M, Chung S, Ashida S, Miki T, Fujioka T, Shuin T, Nakamura Y, Nakagawa H.; ''Novel lipogenic enzyme ELOVL7 is involved in prostate cancer growth through saturated long-chain fatty acid metabolism.''; PubMedEurope PMCScholia
Breckenridge WC, Marai L, Kuksis A.; ''Triglyceride structure of human milk fat.''; PubMedEurope PMCScholia
Cheng D, Chu CH, Chen L, Feder JN, Mintier GA, Wu Y, Cook JW, Harpel MR, Locke GA, An Y, Tamura JK.; ''Expression, purification, and characterization of human and rat acetyl coenzyme A carboxylase (ACC) isozymes.''; PubMedEurope PMCScholia
Zhang L, Joshi AK, Hofmann J, Schweizer E, Smith S.; ''Cloning, expression, and characterization of the human mitochondrial beta-ketoacyl synthase. Complementation of the yeast CEM1 knock-out strain.''; PubMedEurope PMCScholia
Camp LA, Verkruyse LA, Afendis SJ, Slaughter CA, Hofmann SL.; ''Molecular cloning and expression of palmitoyl-protein thioesterase.''; PubMedEurope PMCScholia
Lin R, Tao R, Gao X, Li T, Zhou X, Guan KL, Xiong Y, Lei QY.; ''Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth.''; PubMedEurope PMCScholia
Locke GA, Cheng D, Witmer MR, Tamura JK, Haque T, Carney RF, Rendina AR, Marcinkeviciene J.; ''Differential activation of recombinant human acetyl-CoA carboxylases 1 and 2 by citrate.''; PubMedEurope PMCScholia
Sánchez-Solana B, Li DQ, Kumar R.; ''Cytosolic functions of MORC2 in lipogenesis and adipogenesis.''; PubMedEurope PMCScholia
Steinberg SJ, Morgenthaler J, Heinzer AK, Smith KD, Watkins PA.; ''Very long-chain acyl-CoA synthetases. Human "bubblegum" represents a new family of proteins capable of activating very long-chain fatty acids.''; PubMedEurope PMCScholia
Camp LA, Hofmann SL.; ''Purification and properties of a palmitoyl-protein thioesterase that cleaves palmitate from H-Ras.''; PubMedEurope PMCScholia
Li J, Ding SF, Habib NA, Fermor BF, Wood CB, Gilmour RS.; ''Partial characterization of a cDNA for human stearoyl-CoA desaturase and changes in its mRNA expression in some normal and malignant tissues.''; PubMedEurope PMCScholia
Zhang L, Ge L, Parimoo S, Stenn K, Prouty SM.; ''Human stearoyl-CoA desaturase: alternative transcripts generated from a single gene by usage of tandem polyadenylation sites.''; PubMedEurope PMCScholia
Kirkby B, Roman N, Kobe B, Kellie S, Forwood JK.; ''Functional and structural properties of mammalian acyl-coenzyme A thioesterases.''; PubMedEurope PMCScholia
Leonard AE, Kelder B, Bobik EG, Chuang LT, Lewis CJ, Kopchick JJ, Mukerji P, Huang YS.; ''Identification and expression of mammalian long-chain PUFA elongation enzymes.''; PubMedEurope PMCScholia
Pei Z, Jia Z, Watkins PA.; ''The second member of the human and murine bubblegum family is a testis- and brainstem-specific acyl-CoA synthetase.''; PubMedEurope PMCScholia
Ohno S, Nishikawa K, Honda Y, Nakajin S.; ''Expression in E. coli and tissue distribution of the human homologue of the mouse Ke 6 gene, 17beta-hydroxysteroid dehydrogenase type 8.''; PubMedEurope PMCScholia
Malhotra KT, Malhotra K, Lubin BH, Kuypers FA.; ''Identification and molecular characterization of acyl-CoA synthetase in human erythrocytes and erythroid precursors.''; PubMedEurope PMCScholia
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
Cytosolic acetyl-CoA carboxylase 1 (ACACA) catalyzes the reaction of bicarbonate, ATP, and acetyl-CoA to form malonyl-CoA, ADP, and orthophosphate. The reaction is positively regulated by citrate. The human ACACA cDNA has been cloned (Abu-Elheiga et al. 1995) and the biochemical properties of the human enzyme have recently been described (Cheng et al. 2007; Locke et al. 2008). Four ACACA isoforms generated by alternative splicing have been identified as mRNAs - the protein product of the first has been characterized experimentally. ACACA uses biotin (Btn) and two Mn2+ ions per subunit as cofactors and its activity is increased by polymerisation (Kim et al. 2010, Ingaramo & Beckett 2012). Cytosolic ACACA is thought to maintain regulation of fatty acid synthesis in all tissues but especially lipogenic tissues such as adipose tissue and lactating mammary glands.
Mid1-interacting protein 1 (MID1IP1, aka MIG12, SPOT14R, S14R) plays a role in the regulation of lipogenesis in the liver. It is rapidly upregulated by processes that induce lipogenesis (enhanced glucose metabolism, thyroid hormone administration) (Tsatsos et al. 2008). MID1IP1 forms a heterodimer with thyroid hormone-inducible hepatic protein (THRSP, aka SPOT14, S14), proposed to play the same role in lipogenesis as MID1IP1 (Aipoalani et al. 2010). This complex can polymerise acetyl-CoA carboxylases 1 and 2 (ACACA and B), the first committed enzymes in fatty acid (FA) synthesis. Polymerisation enhances ACACA and ACACB enzyme activities (Kim et al. 2010).
Membrane-associated acyl-CoA synthetase long-chain family members 1,3,5 and 6 (ACSL1,3,5,6) catalyse the conjugation of palmitate (PALM) with CoA to form palmitoyl-CoA (PALM-CoA). Human ACSL1 has not been characterized in detail, but available data suggest that it is associated specifically with the membrane of the endoplasmic reticulum and that it can act on oleic acid as well as on palmitic acid (Malhotra et al. 1999, Fujimoto et al. 2007, Gassler et al. 2007).
Elongation of very long chain fatty acids proteins 1, 2, 3 and 5 (ELOVL1,2,3,5) catalyse the elongation of arachidonyl-CoA (AA-CoA) and malonyl-CoA (Mal-CoA) to form 3-oxo-(7,10,13,16)-docosatetraenoyl-CoA (3ODCT-CoA) (Leonard et al. 2002, Ohno et al. 2010).
The ER membrane-bound elongation of very long chain fatty acids proteins 3, 6 and 7 (ELOVL3,6,7) catalyse the condensation of palmitoyl-CoA (PALM-CoA) with malonyl-CoA (Mal-CoA) to form 3-oxooctadecanoyl-CoA (3OOD-CoA) (Shimamura et al. 2009, Ohno et al. 2010, Naganuma et al. 2011).
Elongation of very long chain fatty acids protein 7 (ELOVL7) catalyzes the reaction of arachidoyl-CoA (C20:0) and malonyl-CoA to form 3-oxobehenoyl-CoA, CO2, and CoASH. ELOVL7 is localized to the endoplasmic reticulum in transfected cells expressing the cloned cDNA (Tamura et al. 2009).
Hydroxysteroid (17-beta) dehydrogenase 12 (HSD17B12) catalyzes the reaction of 3-oxooctadecanoyl-CoA (3-oxostearoyl-CoA) and NADPH + H+ to form 3-hydroxyoctadecanoyl-CoA and NADP+. This activity of HSD17B12 protein and its localization to the endoplasmic reticulum membrane were established in studies of transfected cells expressing the protein (Moon and Horton 2003). Based on the phenotypes of human subjects deficient in the enzyme, HSD17B3 is thought to catalyze the reduction of androstenedione to testosterone (Geissler et al. 1994). A detailed analysis of sequence similarities among the HSD17B protein family reveals close similarity of specificity-determining features of HSD17B12 and HSD12B3, making HSD17B3 a candidate to catalyze 3-OOD-CoA reduction as well (W. Pearson, unpublished, 2012).
Elongation of very long chain fatty acids proteins 1, 4 (ELOVL1,4) catalyse the elongation of lignoceroyl-CoA (TCS-CoA) and malonyl-CoA (Mal-CoA) to form 3-oxocerotoyl-CoA (3OHC-CoA). ELOVL4 is abundant in retinal cells, where it is localized to the endoplasmic reticulum membrane (Grayson & Molday 2005). The catalytic activity of ELOVL4 has not been examined directly but is inferred from that of the homologous mouse protein, which is also active on polyunsaturated fatty acids (PUFAs) (PUFAs) (Agbada et al. 2008).
Trans-2,3-enoyl-CoA reductase (TECR) catalyzes the reaction of trans-octadec-2-enoyl-CoA and NADPH + H+ to form stearoyl-CoA and NADP+. This activity of TECR protein and its localization to the endoplasmic reticulum membrane was established in studies of transfected cells expressing the protein (Moon and Horton 2003).
Acyl-CoA synthetase long-chain family member 4 (ACSL4) associated with the endoplasmic reticulum membrane catalyses the conjugation of arachidonate (AA) with CoA to form arachidonyl-CoA (AA-CoA) (Longo et al. 2003, Meloni et al. 2003). By similarity, ACSL3 can also preferentially conjugate CoA on to AA (Yao & Ye 2008). These enzymes are involved in the activation of long-chain fatty acids for both synthesis of cellular lipids, and degradation via beta-oxidation.
OLAH, a monomeric cytosolic thiolase, catalyzes the hydrolysis of FASN (fatty acid synthase) charged with decanoyl fatty acyl moieties to yield FASN and decanoate (DECA). OLAH expression is confined to the lactating mammary gland, and its catalytic activity enables the early termination of a portion of fatty acid biosynthesis to produce the medium chain-length fatty acids (annotated here as DECA) found in milk (Insull & Ahrens 1959; Breckenridge et al. 1969). OLAH is known only as an open reading frame identified in the human genome and as an mRNA observed in gene expression screening studies. Its biological properties are inferred from those of its well-studied rat ortholog (Libertini & Smith 1978; Mikkelsen et al. 1987).
Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratases 1-4 (PTPLA, B, D1 and D2 respectively, aka HACD1-4) mediate the dehydration step in VLCFA synthesis. A very-long-chain (3R)-3-hydroxyacyl-CoA (VLC3HA-CoA) is dehydrated to a very-long-chain 2,3-trans-enoyl CoA (2,3-TE-CoA) (Ikeda et al. 2008).
The maintenance/regulation of cellular levels of free fatty acids and fatty acyl-CoAs (the activated form of free fatty acids) is extremely important, as imbalances in lipid metabolism can have serious consequences for human health. Free fatty acids can act as detergents to disrupt membranes so their generation is normally tightly regulated to states where they will be rapidly consumed or sequestered. Acyl-coenzyme A thioesterases (ACOTs) hydrolyse the thioester bond in medium- to long-chain fatty acyl-CoAs (of C12-C18 lengths) (MCFAcylCoA, LCFAcylCoA) to their free fatty acids (MCFA, LCFA) (Cohen 2013, Hunt et al. 2012, Kirkby et al. 2010). Lysosomal thioesterase PPT2 is able to specifically hydrolyse palmitoyl-CoA (PALM-CoA) to palmitic acid (PALM) (Soyombo & Hofmann 1997).
The maintenance/regulation of cellular levels of free fatty acids and fatty acyl-CoAs (the activated form of free fatty acids) is extremely important, as imbalances in lipid metabolism can have serious consequences for human health. Free fatty acids can act as detergents to disrupt membranes so their generation is normally tightly regulated to states where they will be rapidly consumed or sequestered. Acyl-coenzyme A thioesterases (ACOTs) hydrolyse the thioester bond in medium- to long-chain fatty acyl-CoAs (of C12-C18 lengths) (MCFAcylCoA, LCFAcylCoA) to their free fatty acids (MCFA, LCFA) (Cohen 2013, Hunt et al. 2012, Kirkby et al. 2010). Lysosomal thioesterase PPT1 is able to specifically hydrolyse palmitic acid (PALM) from palmitoylated proteins (PALM:protein) (Camp & Hofmann 1993, Camp et al. 1994).
Acyl-CoA desaturase (SCD), located on the ER membrane, is the terminal enzyme of the liver microsomal stearyl-CoA desaturase system and is the rate-limiting enzyme in the cellular synthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acids. SCD utilises O2 and electrons from reduced ferrocytochrome b5 (Fe(2+)Cb5) to catalyse the insertion of a double bond into a range of fatty acyl-CoA substrates. This example shows stearoyl-CoA (ST-CoA) desaturation to oleoyl-CoA (OLE-CoA) (Li et al. 1994, Zhang et al. 1999). Studies of tagged recombinant enzyme overexpressed in transiently transfected cells suggest that the enzyme forms dimers and higher oligomers (Zhang et al. 2005).
Long-chain fatty acid-CoA ligases 1 and 2 (ACSBG1 and 2) are capable of activating very long-chain fatty acids (VLCFA) and are thought to play a role in fatty acid metabolism in the brain (ACSBG1 and 2) (Steinberg et al. 2000, Pei et al. 2003), and testes (ACSBG2) (Pei et al. 2006).
Acyl-coenzyme A synthetases (ACSs) catalyse the activation of fatty acids by thioesterification to CoA, the fundamental initial reaction in fatty acid metabolism. Mitochondrial acyl-CoA synthetase family member 3 (ACSF3) preferentially ligates CoA-SH to very long-chain fatty acids (VLCFA), around C24 in length (Watkins et al. 2007).
While fatty acid synthesis from acetyl CoA (Ac-CoA) proceeds in the cytosol, most Ac-CoA in the cell is generated within the mitochondria, by oxidative decarboxylation of the pyruvate derived from glycolysis, as well as from a number of reactions of amino acid catabolism. Mitochondrial Ac-CoA is transported to the cytosol as citrate (CIT) to participate in fatty acid biosynthesis. Cytosolic ATP-citrate synthase (ACLY), in tetrameric form, catalyses the transformation of CIT to Ac-CoA and and plays an essential role in lipogenesis, adipogenesis and differentiation of 3T3-L1 preadipocytic cells (Elshourbagy et al. 1992, Lin et al. 2013). Cytosolic MORC family CW-type zinc finger protein 2 (MORC2) positively regulates the activity of ACLY, thus could be a mediator of lipogenesis, adipogenic differentiation, and lipid homeostasis (Sanchez-Solana et al. 2014).
SLC25A1, in the inner mitochondrial membrane, mediates the exchange of mitochondrial citrate for cytosolic malate (Edvarson et al.2013, Gnoni et al.2009).
Cytosolic fatty acid synthase (FAS) complex catalyzes the reaction of acetyl-CoA with 7 malonyl-CoA and 14 NADHP + 14 H+ to form a molecule of palmitate and 7 CO2, 14 NADP+, 8 CoASH, and 6 H2O. The process proceeds via the successive condensations of malonyl groups onto the growing acyl chain,each followed by loss of CO2 and three steps of reduction (Smith et al. 2003).
Stearoyl-CoA desaturase 5 (SCD5, also known as acyl-CoA desaturase 4), located on the ER membrane, utilises O2 and electrons from reduced ferrocytochrome b5 (Fe(2+)Cb5) to catalyse the insertion of a double bond into a range of fatty acyl-CoA substrates. SCD5 is most abundant in brain and pancreas. The reaction annotated here shows stearoyl-CoA (ST-CoA) desaturation to oleoyl-CoA (OLE-CoA). Studies of tagged recombinant enzyme overexpressed in transiently transfected cells suggest that the enzyme forms dimers and higher oligomers (Wang et al. 2005; Zhang et al. 2005).
Estradiol 17-beta-dehydrogenase 8 (HSD17B8) (Ohno et al. 2008) forms a heterotetramer with carbonyl reductase family member 4 (CBR4) (Chen et al. 2009, Zhang et al. 2005). The heterotetramer has NADPH-dependent 3-ketoacyl-acyl carrier protein reductase activity which is suggested to play a role in biosynthesis of fatty acids in mitochondria (Venkatesan et al. 2014).
Acyl-coenzyme A synthetases catalyse the activation of fatty acids by thioesterification to CoA, the fundamental initial reaction in fatty acid oxidation. Members of the long chain acyl-coenzyme A synthetases (ACSVL) subfamily were originally thought to be fatty acid transport proteins (FATPs), hence their approved gene names and symbols are “solute carrier family 27 (fatty acid transporter) member x" (SLC27Ax) but their transport function has never been proven. Instead, their amino acid sequence contains two highly conserved motifs characteristic of acyl-CoA synthetases. Long-chain fatty acid transport protein 3 (SLC27A3, aka ACSVL3, FATP3) preferentially ligates CoA-SH to very long-chain fatty acids (VLCFA) (Watkins et al. 2007). The activity of human SLC27A3 is inferred from mouse Slc27a3 functional studies (Pei et al. 2004).
Polycistronic transcripts, where a single mRNA can encode several different polypeptide chains, are common in prokaryotes. In humans, only 3 bicistronic transcripts have been characterised to date. Human cDNAs encoding both RPP14 of the RNase P complex and mitochondrial 3-hydroxyacyl thioester dehydratase (HTD2) have been isolated. HTD2 functions in the mitochondrial fatty acid synthesis (FAS) pathway, dehydrating (3R)-hydroxyacyl-CoA (3HA-CoA) to trans-2-enoyl-CoA (t2E-CoA) (Autio et al. 2008).
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Mid1-interacting protein 1 (MID1IP1, aka MIG12, SPOT14R, S14R) plays a role in the regulation of lipogenesis in the liver. It is rapidly upregulated by processes that induce lipogenesis (enhanced glucose metabolism, thyroid hormone administration) (Tsatsos et al. 2008). MID1IP1 forms a heterodimer with thyroid hormone-inducible hepatic protein (THRSP, aka SPOT14, S14), proposed to play the same role in lipogenesis as MID1IP1 (Aipoalani et al. 2010). This complex can polymerise acetyl-CoA carboxylases 1 and 2 (ACACA and B), the first committed enzymes in fatty acid (FA) synthesis. Polymerisation enhances ACACA and ACACB enzyme activities (Kim et al. 2010).