Beta-oxidation begins once fatty acids have been imported into the mitochondrial matrix by carnitine acyltransferases. The beta-oxidation spiral of fatty acids metabolism involves the repetitive removal of two carbon units from the fatty acyl chain. There are four steps to this process: oxidation, hydration, a second oxidation, and finally thiolysis. The last step releases the two-carbon acetyl-CoA and a ready primed acyl-CoA that takes another turn down the spiral. In total each turn of the beta-oxidation spiral produces one NADH, one FADH2, and one acetyl-CoA.
Further oxidation of acetyl-CoA via the tricarboxylic acid cycle generates additional FADH2 and NADH. All reduced cofactors are used by the mitochondrial electron transport chain to form ATP. The complete oxidation of a fatty acid molecule produces numerous ATP molecules. Palmitate, used as the model here, produces 129 ATPs.<p>Beta-oxidation pathways differ for saturated and unsaturated fatty acids. The beta-oxidation of saturated fatty acids requires four different enzymatic steps. Beta-oxidation produces and consumes intermediates with a trans configuration; unsaturated fatty acids that have bonds in the cis configuration require three separate enzymatic steps to prepare these molecules for the beta-oxidation pathway.
View original pathway at Reactome.</div>
Lerner-Ellis JP, Dobson CM, Wai T, Watkins D, Tirone JC, Leclerc D, Doré C, Lepage P, Gravel RA, Rosenblatt DS.; ''Mutations in the MMAA gene in patients with the cblA disorder of vitamin B12 metabolism.''; PubMedEurope PMCScholia
Abe H, Ohtake A, Yamamoto S, Satoh Y, Takayanagi M, Amaya Y, Takiguchi M, Sakuraba H, Suzuki Y, Mori M.; ''Cloning and sequence analysis of a full length cDNA encoding human mitochondrial 3-oxoacyl-CoA thiolase.''; PubMedEurope PMCScholia
Fujino T, Takei YA, Sone H, Ioka RX, Kamataki A, Magoori K, Takahashi S, Sakai J, Yamamoto TT.; ''Molecular identification and characterization of two medium-chain acyl-CoA synthetases, MACS1 and the Sa gene product.''; PubMedEurope PMCScholia
Jiang RC, Qin HD, Zeng MS, Huang W, Feng BJ, Zhang F, Chen HK, Jia WH, Chen LZ, Feng QS, Zhang RH, Yu XJ, Zheng MZ, Zeng YX.; ''A functional variant in the transcriptional regulatory region of gene LOC344967 cosegregates with disease phenotype in familial nasopharyngeal carcinoma.''; PubMedEurope PMCScholia
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Kang HW, Wei J, Cohen DE.; ''PC-TP/StARD2: Of membranes and metabolism.''; PubMedEurope PMCScholia
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Telgmann R, Brand E, Nicaud V, Hagedorn C, Beining K, Schönfelder J, Brink-Spalink V, Schmidt-Petersen K, Matanis T, Vischer P, Nofer JR, Hasenkamp S, Plouin PF, Drouet L, Cambien F, Paul M, Tiret L, Brand-Herrmann SM.; ''SAH gene variants are associated with obesity-related hypertension in Caucasians: the PEGASE Study.''; PubMedEurope PMCScholia
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Stanley CA, Hale DE.; ''Genetic disorders of mitochondrial fatty acid oxidation.''; PubMedEurope PMCScholia
Bobik TA, Rasche ME.; ''Identification of the human methylmalonyl-CoA racemase gene based on the analysis of prokaryotic gene arrangements. Implications for decoding the human genome.''; PubMedEurope PMCScholia
Hansen JS, Faergeman NJ, Kragelund BB, Knudsen J.; ''Acyl-CoA-binding protein (ACBP) localizes to the endoplasmic reticulum and Golgi in a ligand-dependent manner in mammalian cells.''; PubMedEurope PMCScholia
Adams SH, Chui C, Schilbach SL, Yu XX, Goddard AD, Grimaldi JC, Lee J, Dowd P, Colman S, Lewin DA.; ''BFIT, a unique acyl-CoA thioesterase induced in thermogenic brown adipose tissue: cloning, organization of the human gene and assessment of a potential link to obesity.''; PubMedEurope PMCScholia
Worgan LC, Niles K, Tirone JC, Hofmann A, Verner A, Sammak A, Kucic T, Lepage P, Rosenblatt DS.; ''Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype.''; PubMedEurope PMCScholia
Middleton B.; ''The oxoacyl-coenzyme A thiolases of animal tissues.''; PubMedEurope PMCScholia
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Barycki JJ, O'Brien LK, Bratt JM, Zhang R, Sanishvili R, Strauss AW, Banaszak LJ.; ''Biochemical characterization and crystal structure determination of human heart short chain L-3-hydroxyacyl-CoA dehydrogenase provide insights into catalytic mechanism.''; PubMedEurope PMCScholia
Ersoy BA, Tarun A, D'Aquino K, Hancer NJ, Ukomadu C, White MF, Michel T, Manning BD, Cohen DE.; ''Phosphatidylcholine transfer protein interacts with thioesterase superfamily member 2 to attenuate insulin signaling.''; 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
Hunt MC, Ruiter J, Mooyer P, van Roermond CW, Ofman R, Ijlst L, Wanders RJ.; ''Identification of fatty acid oxidation disorder patients with lowered acyl-CoA thioesterase activity in human skin fibroblasts.''; PubMedEurope PMCScholia
Takahashi-Íñiguez T, García-Arellano H, Trujillo-Roldán MA, Flores ME.; ''Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein.''; PubMedEurope PMCScholia
Finocchiaro G, Ito M, Tanaka K.; ''Purification and properties of short chain acyl-CoA, medium chain acyl-CoA, and isovaleryl-CoA dehydrogenases from human liver.''; PubMedEurope PMCScholia
Carpenter K, Pollitt RJ, Middleton B.; ''Human liver long-chain 3-hydroxyacyl-coenzyme A dehydrogenase is a multifunctional membrane-bound beta-oxidation enzyme of mitochondria.''; PubMedEurope PMCScholia
Cheng Z, Song F, Shan X, Wei Z, Wang Y, Dunaway-Mariano D, Gong W.; ''Crystal structure of human thioesterase superfamily member 2.''; PubMedEurope PMCScholia
Bloksgaard M, Neess D, Færgeman NJ, Mandrup S.; ''Acyl-CoA binding protein and epidermal barrier function.''; PubMedEurope PMCScholia
Froese DS, Kochan G, Muniz JR, Wu X, Gileadi C, Ugochukwu E, Krysztofinska E, Gravel RA, Oppermann U, Yue WW.; ''Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation.''; PubMedEurope PMCScholia
CRANE FL, BEINERT H.; ''On the mechanism of dehydrogenation of fatty acyl derivatives of coenzyme A. II. The electron-transferring flavoprotein.''; PubMedEurope PMCScholia
Zhang L, Joshi AK, Smith S.; ''Cloning, expression, characterization, and interaction of two components of a human mitochondrial fatty acid synthase. Malonyltransferase and acyl carrier protein.''; PubMedEurope PMCScholia
Cohen DE.; ''New players on the metabolic stage: How do you like Them Acots?''; PubMedEurope PMCScholia
Kawano Y, Ersoy BA, Li Y, Nishiumi S, Yoshida M, Cohen DE.; ''Thioesterase superfamily member 2 (Them2) and phosphatidylcholine transfer protein (PC-TP) interact to promote fatty acid oxidation and control glucose utilization.''; PubMedEurope PMCScholia
Soupene E, Serikov V, Kuypers FA.; ''Characterization of an acyl-coenzyme A binding protein predominantly expressed in human primitive progenitor cells.''; PubMedEurope PMCScholia
Hunt MC, Siponen MI, Alexson SE.; ''The emerging role of acyl-CoA thioesterases and acyltransferases in regulating peroxisomal lipid metabolism.''; PubMedEurope PMCScholia
Hunt MC, Rautanen A, Westin MA, Svensson LT, Alexson SE.; ''Analysis of the mouse and human acyl-CoA thioesterase (ACOT) gene clusters shows that convergent, functional evolution results in a reduced number of human peroxisomal ACOTs.''; PubMedEurope PMCScholia
Vredendaal PJ, van den Berg IE, Malingré HE, Stroobants AK, Olde Weghuis DE, Berger R.; ''Human short-chain L-3-hydroxyacyl-CoA dehydrogenase: cloning and characterization of the coding sequence.''; PubMedEurope PMCScholia
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Zhao H, Lim K, Choudry A, Latham JA, Pathak MC, Dominguez D, Luo L, Herzberg O, Dunaway-Mariano D.; ''Correlation of structure and function in the human hotdog-fold enzyme hTHEM4.''; PubMedEurope PMCScholia
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Miinalainen IJ, Chen ZJ, Torkko JM, Pirilä PL, Sormunen RT, Bergmann U, Qin YM, Hiltunen JK.; ''Characterization of 2-enoyl thioester reductase from mammals. An ortholog of YBR026p/MRF1'p of the yeast mitochondrial fatty acid synthesis type II.''; PubMedEurope PMCScholia
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Soupene E, Kuypers FA.; ''Ligand binding to the ACBD6 protein regulates the acyl-CoA transferase reactions in membranes.''; PubMedEurope PMCScholia
Padovani D, Banerjee R.; ''Assembly and protection of the radical enzyme, methylmalonyl-CoA mutase, by its chaperone.''; PubMedEurope PMCScholia
Dobson CM, Wai T, Leclerc D, Wilson A, Wu X, Doré C, Hudson T, Rosenblatt DS, Gravel RA.; ''Identification of the gene responsible for the cblA complementation group of vitamin B12-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements.''; PubMedEurope PMCScholia
Kirkby B, Roman N, Kobe B, Kellie S, Forwood JK.; ''Functional and structural properties of mammalian acyl-coenzyme A thioesterases.''; PubMedEurope PMCScholia
Zhuravleva E, Gut H, Hynx D, Marcellin D, Bleck CK, Genoud C, Cron P, Keusch JJ, Dummler B, Esposti MD, Hemmings BA.; ''Acyl coenzyme A thioesterase Them5/Acot15 is involved in cardiolipin remodeling and fatty liver development.''; PubMedEurope PMCScholia
Swarbrick CM, Roman N, Cowieson N, Patterson EI, Nanson J, Siponen MI, Berglund H, Lehtiö L, Forwood JK.; ''Structural basis for regulation of the human acetyl-CoA thioesterase 12 and interactions with the steroidogenic acute regulatory protein-related lipid transfer (START) domain.''; PubMedEurope PMCScholia
Roe CR, Roe DS.; ''Recent developments in the investigation of inherited metabolic disorders using cultured human cells.''; PubMedEurope PMCScholia
Chen ZJ, Pudas R, Sharma S, Smart OS, Juffer AH, Hiltunen JK, Wierenga RK, Haapalainen AM.; ''Structural enzymological studies of 2-enoyl thioester reductase of the human mitochondrial FAS II pathway: new insights into its substrate recognition properties.''; PubMedEurope PMCScholia
Kelley RI.; ''Beta-oxidation of long-chain fatty acids by human fibroblasts: evidence for a novel long-chain acyl-coenzyme A dehydrogenase.''; PubMedEurope PMCScholia
At the beginning of this reaction, 1 molecule of 'cis,cis-3,6-Dodecadienoyl-CoA' is present. At the end of this reaction, 1 molecule of 'trans,cis-Lauro-2,6-dienoyl-CoA ' is present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'dodecenoyl-CoA delta-isomerase activity' of '3,2-trans-enoyl-CoA isomerase Homodimer'.
Three cycles of beta oxidation, each mediated by the activities of trifunctional protein and ACADL tetramer, convert linoleoyl-CoA to cis,cis-3,6-dodecadienoyl-CoA plus three molecules each of CoA-SH, FADH2, and NADH + H+.
One cycle of beta oxidation, each mediated by the activities of trifunctional protein and ACADL tetramer, converts trans,cis-lauro-2,6-dienoyl-CoA to 4-cis-decenoyl-CoA plus molecules of CoA-SH, FADH2, and NADH + H+.
Once the second of the two double bonds has been reached 3,2-trans-enoyl-CoA isomerase, changes the spatial conformation of the second double bond from cis to trans. This step yields trans-dec-2-enoyl-CoA, which then enters the saturated beta-oxidation pathway.
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) (MCFA-CoA, LCFA-CoA) to their free fatty acids (MCFA, LCFA) (Cohen 2013, Hunt et al. 2012, Kirkby et al. 2010). ACOTs that function in the cytosol are ACOT1 (Hunt et al. 2005), ACOT11 (Adams et al. 2001), ACOT12 trimer (Swarbrick et al. 2014), ACOT13 tetramer (Cao et al. 2009, Cheng et al. 2006), ACOT7 hexamer (Hunt et al. 2005b) and ACOT7L dimer (Jiang et al. 2006).
Recent mouse studies reveals a key regulatory role for PCTP in lipid and glucose metabolism. Phosphatidylcholine transfer protein (PCTP aka STARD2) is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain superfamily, a functionally diverse group of proteins that share a unique structural motif for binding lipids. PCTP appears to limit access of fatty acids to mitochondria by binding to (Ersoy et al. 2013) and stimulating the activity of acyl-coenzyme A thioesterase 13 (ACOT13, aka Acyl-CoA thioesterase 13, THEM2), an enzyme that catalyses the hydrolysis of acyl-CoAs to their free fatty acids (Kawano et al. 2014). Ultimately, insulin signaling is downregulated (Kang et al. 2010).
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. Acyl-coenzyme A thioesterases (ACOTs) hydrolyse the thioester bond in medium- to long-chain fatty acyl-CoAs (of C12-C18 lengths) (MCFA-CoA, LCFA-CoA) to their free fatty acids (MCFA, LCFA) (Cohen 2013, Hunt et al. 2012, Kirkby et al. 2010). ACOTs that function in the mitochondrion are ACOT2 (Hunt et al. 2006), ACOT9 (Kirkby et al. 2010), THEM4 dimer (Zhuravleva et al. 2012, Zhao et al. 2012) and THEM5 dimer (Zhuravleva et al. 2012). THEM4 is also functional in the cytosol and at the plasma membrane (Cohen 2013).
Acyl-CoA dehydrogenase family member 10 (ACAD10) is a mitochondrial enzyme that can catalyse the alpha, beta-dehydrogenation of acyl-CoA esters. ACAD10 shows highest expression in foetal brain and is shown to be active only on S-2-methylpentadecenoyl-CoA (S-2MPDA-CoA), a C15 acyl-CoA. The S isomer is dehydrogenated to its respective 2,3-dehydroacyl-CoA product, S-2methyl-2,3-dehydropentadecenoyl-CoA (S-2MDPDA) (He et al. 2011).
Acyl-CoA dehydrogenase family member 11 (ACAD11) is a mitochondrial membrane-bound enzyme that can catalyse the alpha, beta-dehydrogenation of acyl-CoA esters. ACAD11 shows highest expression in the brain and is shown to dehydrogenate the C22 acyl-CoA behenoyl-CoA (BH-CoA) to 2,3-dehydrobehenoyl-CoA (DBH-CoA) (He et al. 2011).
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 2 (ACSF2) preferentially ligates CoA-SH to medium-chain fatty acids (MCFA), around C8 in length (Watkins et al. 2007).
Methylmalonyl CoA mutase (MUT aka MCM) (Jansen et al. 1989) utilises adenosylcobalamin (AdoCbl) as a cofactor and catalyzes interchange of a carbonyl-CoA group and a hydrogen atom in conversion of methylmalonyl CoA to form succinyl CoA, a precursor for the citric acid cycle. MUT has a homodimeric structure and is located in the mitochondrial matrix. Defects in MUT cause methylmalonic aciduria, mut type (MMAM; MIM:251000), an often fatal disorder of organic acid metabolism (Worgan et al. 2006).
Methylmalonic aciduria type A protein (MMAA) is thought to act as a chaperone to MUT, the enzyme which utilises adenosylcobalamin (AdoCbl) as a cofactor. MMAA is suggested to play a dual role with regards to MUT protection and reactivation. Some AdoCbl-dependent enzymes undergo suicide inactivation after catalysis due to the oxidative inactivation of Cbl. MMAA is thought to play a protective role to prevent MUT being inactivated in this way. After the catalytic cycle when MUT is inactive, MMAA increases the enzymatic activity of MUT through exchange of the damaged cofactor. Whether this happens via GTP-mediated hydrolysis is unknown at present (Takahashi-Iniguez et al. 2011, Froese et al. 2010). Bacterial AdoCbl-containing enzymes possess reactivating factors which release the inactivated cofactor to allow the resulting apoenzyme to reconstitute into an active form. A bacterial orthologue of MMAA, MeaB, forms a stable complex with MUT and plays a role in its protection and reactivation (Padovani & Banerjee 2006).
Defects in MMAA cause methylmalonic aciduria type cblA (cblA aka methylmalonic aciduria type A or vitamin B12-responsive methylmalonicaciduria of cblA complementation type; MIM:251100). Affected individuals accumulate methylmalonic acid in the blood and urine and are prone to potentially life threatening acidotic crises in infancy or early childhood (Dobson et al. 2002, Lerner-Ellis et al. 2004).
At the beginning of this reaction, 1 molecule of 'D-methylmalonyl-CoA' is present. At the end of this reaction, 1 molecule of 'L-methylmalonyl-CoA' is present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'methylmalonyl-CoA epimerase activity' of 'methylmalonyl-CoA epimerase'.
Propionyl CoA carboxylase in the mitochondrial matrix catalyzes the reaction of propionyl-CoA, CO2, and ATP to form D-methylmalonyl-CoA, ADP, and orthophosphate. The active form of the enzyme is a heteromultimer, probably consisting of six alpha subunits each bound to a biotin molecule and six beta subunits (Kaziro et al. 1961; Kalousek et al. 1980; Fenton et al. 2001). Both alpha and beta subunits are posttranslationally modified to remove amino-terminal mitochondrial import sequences (Stadler et al. 2005).
At the beginning of this reaction, 1 molecule of '(S)-3-Hydroxydodecanoyl-CoA', and 1 molecule of 'NAD+' are present. At the end of this reaction, 1 molecule of 'H+', 1 molecule of '3-Oxododecanoyl-CoA', and 1 molecule of 'NADH' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'short chain 3-hydroxyacyl-CoA dehydrogenase homodimer'.
At the beginning of this reaction, 1 molecule of '2-trans-Dodecenoyl-CoA', and 1 molecule of 'H2O' are present. At the end of this reaction, 1 molecule of '(S)-3-Hydroxydodecanoyl-CoA' is present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'enoyl-CoA hydratase hexamer'.
At the beginning of this reaction, 1 molecule of 'Lauroyl-CoA', and 1 molecule of 'FAD' are present. At the end of this reaction, 1 molecule of 'FADH2', and 1 molecule of '2-trans-Dodecenoyl-CoA' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'LCAD acyl-CoA dehydrogenase homotetramer'.
At the beginning of this reaction, 1 molecule of '3-Oxotetradecanoyl-CoA', and 1 molecule of 'CoA' are present. At the end of this reaction, 1 molecule of 'Lauroyl-CoA', and 1 molecule of 'Acetyl-CoA' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.
At the beginning of this reaction, 1 molecule of 'myristoyl-CoA', and 1 molecule of 'FAD' are present. At the end of this reaction, 1 molecule of 'FADH2', and 1 molecule of 'trans-Tetradec-2-enoyl-CoA' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'LCAD acyl-CoA dehydrogenase homotetramer'.
At the beginning of this reaction, 1 molecule of 'trans-Tetradec-2-enoyl-CoA', and 1 molecule of 'H2O' are present. At the end of this reaction, 1 molecule of '(S)-3-Hydroxytetradecanoyl-CoA' is present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'Trifunctional Protein'.
At the beginning of this reaction, 1 molecule of 'NAD+', and 1 molecule of '(S)-3-Hydroxytetradecanoyl-CoA' are present. At the end of this reaction, 1 molecule of 'H+', 1 molecule of '3-Oxotetradecanoyl-CoA', and 1 molecule of 'NADH' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'Trifunctional Protein'.
At the beginning of this reaction, 1 molecule of 'palmitoyl-CoA', and 1 molecule of 'FAD' are present. At the end of this reaction, 1 molecule of 'FADH2', and 1 molecule of 'trans-Hexadec-2-enoyl-CoA' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'VLCAD acyl-CoA dehydrogenase homodimer'.
At the beginning of this reaction, 1 molecule of 'H2O', and 1 molecule of 'trans-Hexadec-2-enoyl-CoA' are present. At the end of this reaction, 1 molecule of '(S)-3-Hydroxyhexadecanoyl-CoA' is present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'Trifunctional Protein'.
At the beginning of this reaction, 1 molecule of 'NAD+', and 1 molecule of '(S)-3-Hydroxyhexadecanoyl-CoA' are present. At the end of this reaction, 1 molecule of '3-Oxopalmitoyl-CoA', 1 molecule of 'H+', and 1 molecule of 'NADH' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'Trifunctional Protein'.
At the beginning of this reaction, 1 molecule of '3-Oxopalmitoyl-CoA', and 1 molecule of 'CoA' are present. At the end of this reaction, 1 molecule of 'Acetyl-CoA', and 1 molecule of 'myristoyl-CoA' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.
At the beginning of this reaction, 1 molecule of '3-Oxododecanoyl-CoA', and 1 molecule of 'CoA' are present. At the end of this reaction, 1 molecule of 'Decanoyl-CoA', and 1 molecule of 'Acetyl-CoA' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.
At the beginning of this reaction, 1 molecule of 'NAD+', and 1 molecule of '(S)-3-Hydroxybutanoyl-CoA' are present. At the end of this reaction, 1 molecule of 'acetoacetyl-CoA', 1 molecule of 'H+', and 1 molecule of 'NADH' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'short chain 3-hydroxyacyl-CoA dehydrogenase homodimer'.
At the beginning of this reaction, 1 molecule of 'Crotonoyl-CoA', and 1 molecule of 'H2O' are present. At the end of this reaction, 1 molecule of '(S)-3-Hydroxybutanoyl-CoA' is present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'enoyl-CoA hydratase hexamer'.
At the beginning of this reaction, 1 molecule of 'FAD', and 1 molecule of 'Butanoyl-CoA' are present. At the end of this reaction, 1 molecule of 'Crotonoyl-CoA', and 1 molecule of 'FADH2' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'SCAD acyl-CoA dehydrogenase homotetramer'.
At the beginning of this reaction, 1 molecule of '3-Oxohexanoyl-CoA', and 1 molecule of 'CoA' are present. At the end of this reaction, 1 molecule of 'Acetyl-CoA', and 1 molecule of 'Butanoyl-CoA' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.
At the beginning of this reaction, 1 molecule of 'NAD+', and 1 molecule of '(S)-Hydroxyhexanoyl-CoA' are present. At the end of this reaction, 1 molecule of '3-Oxohexanoyl-CoA', 1 molecule of 'H+', and 1 molecule of 'NADH' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'short chain 3-hydroxyacyl-CoA dehydrogenase homodimer'.
At the beginning of this reaction, 1 molecule of 'trans-Hex-2-enoyl-CoA', and 1 molecule of 'H2O' are present. At the end of this reaction, 1 molecule of '(S)-Hydroxyhexanoyl-CoA' is present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'enoyl-CoA hydratase hexamer'.
At the beginning of this reaction, 1 molecule of 'Hexanoyl-CoA', and 1 molecule of 'FAD' are present. At the end of this reaction, 1 molecule of 'trans-Hex-2-enoyl-CoA', and 1 molecule of 'FADH2' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'SCAD acyl-CoA dehydrogenase homotetramer'.
At the beginning of this reaction, 1 molecule of '3-Oxooctanoyl-CoA', and 1 molecule of 'CoA' are present. At the end of this reaction, 1 molecule of 'Hexanoyl-CoA', and 1 molecule of 'Acetyl-CoA' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.
At the beginning of this reaction, 1 molecule of 'NAD+', and 1 molecule of '(S)-Hydroxyoctanoyl-CoA' are present. At the end of this reaction, 1 molecule of '3-Oxooctanoyl-CoA', 1 molecule of 'H+', and 1 molecule of 'NADH' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'short chain 3-hydroxyacyl-CoA dehydrogenase homodimer'.
At the beginning of this reaction, 1 molecule of 'H2O', and 1 molecule of 'trans-Oct-2-enoyl-CoA' are present. At the end of this reaction, 1 molecule of '(S)-Hydroxyoctanoyl-CoA' is present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'enoyl-CoA hydratase hexamer'.
At the beginning of this reaction, 1 molecule of 'Octanoyl-CoA', and 1 molecule of 'FAD' are present. At the end of this reaction, 1 molecule of 'FADH2', and 1 molecule of 'trans-Oct-2-enoyl-CoA' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'MCAD acyl-CoA dehydrogenase homotetramer'.
At the beginning of this reaction, 1 molecule of '3-Oxodecanoyl-CoA', and 1 molecule of 'CoA' are present. At the end of this reaction, 1 molecule of 'Acetyl-CoA', and 1 molecule of 'Octanoyl-CoA' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.
At the beginning of this reaction, 1 molecule of '(S)-Hydroxydecanoyl-CoA', and 1 molecule of 'NAD+' are present. At the end of this reaction, 1 molecule of 'H+', 1 molecule of '3-Oxodecanoyl-CoA', and 1 molecule of 'NADH' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'short chain 3-hydroxyacyl-CoA dehydrogenase homodimer'.
At the beginning of this reaction, 1 molecule of 'trans-Dec-2-enoyl-CoA', and 1 molecule of 'H2O' are present. At the end of this reaction, 1 molecule of '(S)-Hydroxydecanoyl-CoA' is present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'enoyl-CoA hydratase hexamer'.
At the beginning of this reaction, 1 molecule of 'Decanoyl-CoA', and 1 molecule of 'FAD' are present. At the end of this reaction, 1 molecule of 'trans-Dec-2-enoyl-CoA', and 1 molecule of 'FADH2' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'MCAD acyl-CoA dehydrogenase homotetramer'.
Acyl-CoA-binding protein (DBI, aka ACBP) can bind medium- and long-chain acyl-CoA esters (MCFA-CoA, LCFA-CoA) with very high affinity. It is localised to the ER (and Golgi) and may function as an intracellular carrier of acyl-CoA esters (Hansen et al. 2008, Bloksgaard et al. 2014). Acyl-CoA-binding domain-containing protein 7 (ACBD7) shares around 60% sequence homology with DBI and is proposed to also bind fatty acyl-CoAs but its function is yet to be determined.
Acyl-CoA-binding domain-containing protein 6 (ACBD6) has an acyl-CoA binding domain at its N terminus and two ankyrin motifs at its C terminus. ACBD6 binds long-chain acyl-CoAs (LCFA-CoA) with a strong preference for unsaturated, C18:1-CoA and C20:4-CoA, over saturated, C16:0-CoA substrates. ACBD6 is expressed in tissues and progenitor cells with functions in blood and vessel development (Soupene et al. 2008). A possible role of ACBD6 could be to protect membrane systems from the detergent nature of free acyl-CoAs by controlling their release to acyl-CoA-utilising enzymes (Soupene & Kuypers 2015).
Mitochondrial 3-ketoacyl-CoA thiolase (ACAA2) is a mitochondrial matrix enzyme involved in fatty acid beta-oxidation, transferring the acyl group from acyl-CoA (acyl-CoA) to acetyl-CoA (Ac-CoA) to form 3-oxyoacyl-CoA (3OA-CoA) and CoA-SH (Abe et al. 1993, Middleton 1973).
Mitochondrial acyl-coenzyme A synthetase ACSM3 (aka protein SAH homolog) is expressed in the mitochondrial matrix and possesses medium-chain fatty acid:CoA ligase activity. Based on characterisation experiments in mice, ACSM3 preferentially ligates C2-C6 fatty acids, especially butyrate (BUT, a C4 fatty acid) (Fujino et al. 2001). The product, butyryl-CoA (BT-CoA) is used in beta oxidation. ACSM3 gene variants may be associated with obesity-related hypertension (Iwai et al. 1994, 2002, Telgmann et al. 2007, Tikhonoff et al. 2008). The mechanisms by which ACSM3 gene variants affect blood pressure remain to be elucidated.
Mitochondrial acyl-coenzyme A synthetase ACSM6 is proposed to be located in the mitochondrial matrix and possess the same medium-chain fatty acid:CoA ligase activity as ACSM3.
The ACP (acyl carrier protein) NDUFAB1 is the cofactor protein that covalently binds all fatty acyl intermediates via a phosphopantetheine linkage during the synthesis of fatty acids. Mitochondrial malonyl-CoA-acyl carrier protein transacylase (MCAT, MT) catalyses the transfer of a malonyl moiety from malonyl-CoA (Mal-CoA) to the free thiol group of the phosphopantetheine arm of NDUFAB1, suggesting a possible role in fatty acid biosynthesis in the mitochondrion (Zhang et al. 2003).
Mitochondrial trans-2-enoyl-CoA reductase (MECR aka NBRF1) is a dimeric oxidoreductase with a preference for short and medium chain trans fatty acyl-CoA substrates and may play a role in mitochondrial fatty acid synthesis (Chen et al. 2008). MECR is able to reduce trans acyl-CoA substrates of chain length C6 to C16 in an NADPH-dependent manner (Miinalainen et al. 2003). A representative reaction described here is the reduction of trans-dec-2-enoyl-CoA (tdec2-CoA) to decanoyl-CoA (DEC-CoA).
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This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'dodecenoyl-CoA delta-isomerase activity' of '3,2-trans-enoyl-CoA isomerase Homodimer'.
Recent mouse studies reveals a key regulatory role for PCTP in lipid and glucose metabolism. Phosphatidylcholine transfer protein (PCTP aka STARD2) is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain superfamily, a functionally diverse group of proteins that share a unique structural motif for binding lipids. PCTP appears to limit access of fatty acids to mitochondria by binding to (Ersoy et al. 2013) and stimulating the activity of acyl-coenzyme A thioesterase 13 (ACOT13, aka Acyl-CoA thioesterase 13, THEM2), an enzyme that catalyses the hydrolysis of acyl-CoAs to their free fatty acids (Kawano et al. 2014). Ultimately, insulin signaling is downregulated (Kang et al. 2010).
Methylmalonic aciduria type A protein (MMAA) is thought to act as a chaperone to MUT, the enzyme which utilises adenosylcobalamin (AdoCbl) as a cofactor. MMAA is suggested to play a dual role with regards to MUT protection and reactivation. Some AdoCbl-dependent enzymes undergo suicide inactivation after catalysis due to the oxidative inactivation of Cbl. MMAA is thought to play a protective role to prevent MUT being inactivated in this way. After the catalytic cycle when MUT is inactive, MMAA increases the enzymatic activity of MUT through exchange of the damaged cofactor. Whether this happens via GTP-mediated hydrolysis is unknown at present (Takahashi-Iniguez et al. 2011, Froese et al. 2010). Bacterial AdoCbl-containing enzymes possess reactivating factors which release the inactivated cofactor to allow the resulting apoenzyme to reconstitute into an active form. A bacterial orthologue of MMAA, MeaB, forms a stable complex with MUT and plays a role in its protection and reactivation (Padovani & Banerjee 2006).
Defects in MMAA cause methylmalonic aciduria type cblA (cblA aka methylmalonic aciduria type A or vitamin B12-responsive methylmalonicaciduria of cblA complementation type; MIM:251100). Affected individuals accumulate methylmalonic acid in the blood and urine and are prone to potentially life threatening acidotic crises in infancy or early childhood (Dobson et al. 2002, Lerner-Ellis et al. 2004).
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'methylmalonyl-CoA epimerase activity' of 'methylmalonyl-CoA epimerase'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'short chain 3-hydroxyacyl-CoA dehydrogenase homodimer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'enoyl-CoA hydratase hexamer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'LCAD acyl-CoA dehydrogenase homotetramer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'LCAD acyl-CoA dehydrogenase homotetramer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'Trifunctional Protein'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'Trifunctional Protein'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'VLCAD acyl-CoA dehydrogenase homodimer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'Trifunctional Protein'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'Trifunctional Protein'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'short chain 3-hydroxyacyl-CoA dehydrogenase homodimer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'enoyl-CoA hydratase hexamer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'SCAD acyl-CoA dehydrogenase homotetramer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'short chain 3-hydroxyacyl-CoA dehydrogenase homodimer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'enoyl-CoA hydratase hexamer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'SCAD acyl-CoA dehydrogenase homotetramer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'short chain 3-hydroxyacyl-CoA dehydrogenase homodimer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'enoyl-CoA hydratase hexamer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'MCAD acyl-CoA dehydrogenase homotetramer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'short chain 3-hydroxyacyl-CoA dehydrogenase homodimer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'enoyl-CoA hydratase hexamer'.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'MCAD acyl-CoA dehydrogenase homotetramer'.
Mitochondrial acyl-coenzyme A synthetase ACSM6 is proposed to be located in the mitochondrial matrix and possess the same medium-chain fatty acid:CoA ligase activity as ACSM3.