Catalyzes the formation of fatty acid-cholesterol esters, which are less soluble in membranes than cholesterol (PubMed:16154994, PubMed:16647063, PubMed:32433613, PubMed:32433614, PubMed:32944968, PubMed:9020103). Plays a role in lipoprotein assembly and dietary cholesterol absorption (PubMed:16154994, PubMed:9020103). Preferentially utilizes oleoyl-CoA ((9Z)-octadecenoyl-CoA) as a substrate: shows a higher activity towards an acyl-CoA substrate with a double bond at the delta-9 position (9Z) th

Endoplasmic reticulum membrane

Lysosomal membrane protein that transports cobalamin (Vitamin B12) from the lysosomal lumen to the cytosol in an ATP-dependent manner (PubMed:22922874, PubMed:28572511, PubMed:31467407, PubMed:33845046). Targeted by LMBRD1 lysosomal chaperone from the endoplasmic reticulum to the lysosomal membrane (PubMed:27456980). Then forms a complex with lysosomal chaperone LMBRD1 and cytosolic MMACHC to transport cobalamin across the lysosomal membrane (PubMed:25535791)

Endoplasmic reticulum membraneLysosome membrane

Methylmalonic aciduria and homocystinuria type cblJ

A disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Clinical features include feeding difficulties, poor growth, hypotonia, lethargy, anemia, and developmental delay.

This is one of the 2 subunits of the biotin-dependent propionyl-CoA carboxylase (PCC), a mitochondrial enzyme involved in the catabolism of odd chain fatty acids, branched-chain amino acids isoleucine, threonine, methionine, and valine and other metabolites (PubMed:6765947, PubMed:8434582). Propionyl-CoA carboxylase catalyzes the carboxylation of propionyl-CoA/propanoyl-CoA to D-methylmalonyl-CoA/(S)-methylmalonyl-CoA (PubMed:10101253, PubMed:6765947, PubMed:8434582). Within the holoenzyme, the

Mitochondrion matrix

Propionic acidemia type I

Life-threatening disease characterized by episodic vomiting, lethargy and ketosis, neutropenia, periodic thrombocytopenia, hypogammaglobulinemia, developmental retardation, and intolerance to protein.

Hydrolyzes 3-hydroxyisobutyryl-CoA (HIBYL-CoA), a saline catabolite. Has high activity toward isobutyryl-CoA. Could be an isobutyryl-CoA dehydrogenase that functions in valine catabolism. Also hydrolyzes 3-hydroxypropanoyl-CoA

Mitochondrion

3-hydroxyisobutryl-CoA hydrolase deficiency

An autosomal recessive inborn error of valine metabolism. It causes severely delayed psychomotor development, neurodegeneration, increased lactic acid, and brain lesions in the basal ganglia.

Catalytic release of biotin from biocytin, the product of biotin-dependent carboxylases degradation

Secreted, extracellular space

Biotinidase deficiency

A juvenile form of multiple carboxylase deficiency, an autosomal recessive disorder of biotin metabolism, characterized by ketoacidosis, hyperammonemia, excretion of abnormal organic acid metabolites, and dermatitis. Biotinidase deficiency is characterized by seizures, hypotonia, skin rash, alopecia, ataxia, hearing loss, and optic atrophy. If untreated, symptoms usually become progressively worse, and coma and death may occur.

Involved in cobalamin metabolism and trafficking (PubMed:18385497, PubMed:23415655, PubMed:24722857, PubMed:26364851). Plays a role in regulating the biosynthesis and the proportion of two coenzymes, methylcob(III)alamin (MeCbl) and 5'-deoxyadenosylcobalamin (AdoCbl) (PubMed:18385497, PubMed:23415655, PubMed:24722857). Promotes oxidation of cob(II)alamin bound to MMACHC (PubMed:26364851). The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMA

CytoplasmMitochondrion

Methylmalonic aciduria and homocystinuria, cblD type

An autosomal recessive disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Clinical features include developmental delay, hyotonia, intellectual disability, seizures, and megaloblastic anemia. Laboratory studies show methylmalonic aciduria and homocystinuria.

Short and branched chain specific acyl-CoA dehydrogenase that catalyzes the proR-proR stereospecific alpha,beta-dehydrogenation of fatty acyl-CoA thioesters using the electron transfer flavoprotein (ETF) as their physiologic electron acceptor, resulting in the formation of trans-2-enoyl-CoA ((2E)-enoyl-CoA) (PubMed:10832746, PubMed:11013134, PubMed:21430231, PubMed:7698750). Among the different mitochondrial acyl-CoA dehydrogenases, acts specifically on short and branched chain acyl-CoA derivati

Mitochondrion matrix

Short/branched-chain acyl-CoA dehydrogenase deficiency

Autosomal recessive disorder and consists of a defect in catabolism of L-isoleucine which is characterized by an increase of 2-methylbutyrylglycine and 2-methylbutyrylcarnitine in blood and urine. Affected individuals have seizures and psychomotor delay as the main clinical features.

This is one of the 2 subunits of the biotin-dependent propionyl-CoA carboxylase (PCC), a mitochondrial enzyme involved in the catabolism of odd chain fatty acids, branched-chain amino acids isoleucine, threonine, methionine, and valine and other metabolites (PubMed:15890657, PubMed:6765947). Propionyl-CoA carboxylase catalyzes the carboxylation of propionyl-CoA/propanoyl-CoA to D-methylmalonyl-CoA/(S)-methylmalonyl-CoA (PubMed:15890657, PubMed:6765947). Within the holoenzyme, the alpha subunit c

Mitochondrion matrix

Propionic acidemia type II

Life-threatening disease characterized by episodic vomiting, lethargy and ketosis, neutropenia, periodic thrombocytopenia, hypogammaglobulinemia, developmental retardation, and intolerance to protein.

Essential component of the TIM23 complex, a complex that mediates the translocation of transit peptide-containing proteins across the mitochondrial inner membrane (PubMed:30190335, PubMed:38828998). Has some phosphatase activity in vitro; however such activity may not be relevant in vivo May participate in the release of snRNPs and SMN from the Cajal body

Mitochondrion inner membraneNucleus speckle

3-methylglutaconic aciduria 9

An autosomal recessive disease characterized by early-onset seizures, severely delayed psychomotor development and intellectual disability. Patients have hypotonia or spasticity, and laboratory investigations show increased serum lactate and 3-methylglutaconic aciduria.

Acyltransferase required to remodel newly synthesized phospholipid cardiolipin (1',3'-bis-[1,2-diacyl-sn-glycero-3-phospho]-glycerol or CL), a key component of the mitochondrial inner membrane, with tissue specific acyl chains necessary for adequate mitochondrial function (PubMed:12930833, PubMed:19164547, PubMed:19700766, PubMed:26908608, PubMed:33096711). Its role in cellular physiology is to improve mitochondrial performance (PubMed:32234310). CL is critical for the coassembly of lipids and p

Mitochondrion outer membraneMitochondrion inner membraneMitochondrion membraneCytoplasm

Barth syndrome

An X-linked disease characterized by dilated cardiomyopathy with endocardial fibroelastosis, a predominantly proximal skeletal myopathy, growth retardation, neutropenia, and organic aciduria, particularly excess of 3-methylglutaconic acid. Additional features include hypertrophic cardiomyopathy, isolated left ventricular non-compaction, ventricular arrhythmia, motor delay, poor appetite, fatigue and exercise intolerance, hypoglycemia, lactic acidosis, hyperammonemia, and dramatic late catch-up growth after growth delay throughout childhood.

Biotin--protein ligase catalyzing the biotinylation of the 4 biotin-dependent carboxylases acetyl-CoA-carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase, and methylcrotonyl-CoA carboxylase

CytoplasmMitochondrion

Holocarboxylase synthetase deficiency

A neonatal form of multiple carboxylase deficiency, an autosomal recessive disorder of biotin metabolism, characterized by ketoacidosis, hyperammonemia, excretion of abnormal organic acid metabolites, and dermatitis. In holocarboxylase synthetase deficiency, clinical and biochemical symptoms improve dramatically with administration of biotin.

Converts cob(I)alamin to adenosylcobalamin (adenosylcob(III)alamin), a coenzyme for methylmalonyl-CoA mutase, therefore participates in the final step of the vitamin B12 conversion (PubMed:12514191). Generates adenosylcobalamin (AdoCbl) and directly delivers the cofactor to MUT in a transfer that is stimulated by ATP-binding to MMAB and gated by MMAA (Probable)

Mitochondrion

Methylmalonic aciduria, cblB type

An autosomal recessive disorder of methylmalonate and cobalamin metabolism due to defective synthesis of adenosylcobalamin.

Functions as a regulatory ATPase and participates in secretion/protein trafficking process. Has ATP-dependent protein disaggregase activity and is required to maintain the solubility of key mitochondrial proteins (PubMed:32573439, PubMed:34115842, PubMed:35247700, PubMed:36170828, PubMed:36745679). Involved in mitochondrial-mediated antiviral innate immunity, activates RIG-I-mediated signal transduction and production of IFNB1 and pro-inflammatory cytokine IL6 (PubMed:31522117). Plays a role in

Mitochondrion intermembrane space

3-methylglutaconic aciduria 7B

An autosomal recessive inborn error of metabolism with a highly variable phenotype. Primary disease symptoms are increased levels of 3-methylglutaconic acid, neurologic deterioration and neutropenia. Other common features include progressive encephalopathy, movement abnormalities, delayed psychomotor development,impaired intellectual development, cataracts, seizures, and recurrent infections.

Lysosomal membrane chaperone required to export cobalamin (vitamin B12) from the lysosome to the cytosol, allowing its conversion to cofactors (PubMed:19136951). Targets ABCD4 transporter from the endoplasmic reticulum to the lysosome (PubMed:27456980). Then forms a complex with lysosomal ABCD4 and cytoplasmic MMACHC to transport cobalamin across the lysosomal membrane (PubMed:25535791). Acts as an adapter protein which plays an important role in mediating and regulating the internalization of t

Endoplasmic reticulum membraneLysosome membraneCell membraneCytoplasmic vesicle, clathrin-coated vesicle

Methylmalonic aciduria and homocystinuria, cblF type

An autosomal recessive disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). It is due to accumulation of free cobalamin in lysosomes, thus hindering its conversion to cofactors. Clinical features include developmental delay, stomatitis, glossitis, seizures and methylmalonic aciduria responsive to vitamin B12.

Transcriptional coregulator (By similarity). Serves as a scaffold protein, bridging interactions between transcription factors, including THAP11 and ZNF143, and transcriptional coregulators (PubMed:26416877). Involved in control of the cell cycle (PubMed:10629049, PubMed:10779346, PubMed:15190068, PubMed:16624878, PubMed:23629655). Also antagonizes transactivation by ZBTB17 and GABP2; represses ZBTB17 activation of the p15(INK4b) promoter and inhibits its ability to recruit p300 (PubMed:10675337

CytoplasmNucleus

Methylmalonic aciduria and homocystinuria, cblX type

An X-linked recessive metabolic disorder characterized by severely delayed psychomotor development apparent in infancy, failure to thrive, impaired intellectual development, and intractable epilepsy. Additional features may include microcephaly and choreoathetosis.

Cobalamin (vitamin B12) cytosolic chaperone that catalyzes the reductive decyanation of cyanocob(III)alamin (cyanocobalamin, CNCbl) to yield cob(II)alamin and cyanide, using FAD or FMN as cofactors and NADPH as cosubstrate (PubMed:18779575, PubMed:19700356, PubMed:21697092, PubMed:25809485). Cyanocobalamin constitutes the inactive form of vitamin B12 introduced from the diet, and is converted into the active cofactors methylcobalamin (MeCbl) involved in methionine biosynthesis, and 5'-deoxyadeno

Cytoplasm, cytosol

Methylmalonic aciduria and homocystinuria, cblC type

An autosomal recessive disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Affected individuals may have developmental, hematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood.

Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides and as sensor of hydrogen peroxide-mediated signaling events. Might participate in the signaling cascades of growth factors and tumor necrosis factor-alpha by regulating the intracellular concentrations of H(2)O(2) (PubMed:9497357). Reduces an intramolecular disulfide bond in G

CytoplasmMelanosome

Catalyzes the reversible isomerization of methylmalonyl-CoA (MMCoA) (generated from branched-chain amino acid metabolism and degradation of dietary odd chain fatty acids and cholesterol) to succinyl-CoA (3-carboxypropionyl-CoA), a key intermediate of the tricarboxylic acid cycle

Mitochondrion matrixMitochondrionCytoplasm

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

An often fatal disorder of organic acid metabolism. Common clinical features include lethargy, vomiting, failure to thrive, hypotonia, neurological deficit and early death. Two forms of the disease are distinguished by the presence (mut-) or absence (mut0) of residual enzyme activity. Mut0 patients have more severe neurological manifestations of the disease than do MUT- patients. MAMM is unresponsive to vitamin B12 therapy.

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase that catalyzes a cation-dependent cleavage of (S)-3-hydroxy-3-methylglutaryl-CoA into acetyl-CoA and acetoacetate, a key step in ketogenesis. Terminal step in leucine catabolism. Ketone bodies (beta-hydroxybutyrate, acetoacetate and acetone) are essential as an alternative source of energy to glucose, as lipid precursors and as regulators of metabolism

Mitochondrion matrixPeroxisome

3-hydroxy-3-methylglutaryl-CoA lyase deficiency

An autosomal recessive disease affecting ketogenesis and L-leucine catabolism. The disease usually appears in the first year of life after a fasting period and its clinical acute symptoms include vomiting, seizures, metabolic acidosis, hypoketotic hypoglycemia and lethargy. These symptoms sometimes progress to coma, with fatal outcome in some cases.

Carboxyltransferase subunit of the 3-methylcrotonyl-CoA carboxylase, an enzyme that catalyzes the conversion of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA, a critical step for leucine and isovaleric acid catabolism

Mitochondrion matrix

3-methylcrotonoyl-CoA carboxylase 2 deficiency

An autosomal recessive disorder of leucine catabolism. The phenotype is variable, ranging from neonatal onset with severe neurological involvement to asymptomatic adults. There is a characteristic organic aciduria with massive excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, usually in combination with a severe secondary carnitine deficiency.

Biotin-attachment subunit of the 3-methylcrotonyl-CoA carboxylase, an enzyme that catalyzes the conversion of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA, a critical step for leucine and isovaleric acid catabolism

Mitochondrion matrix

3-methylcrotonoyl-CoA carboxylase 1 deficiency

An autosomal recessive disorder of leucine catabolism. The phenotype is variable, ranging from neonatal onset with severe neurological involvement to asymptomatic adults. There is a characteristic organic aciduria with massive excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, usually in combination with a severe secondary carnitine deficiency.

Serine protease that shows proteolytic activity against a non-specific substrate beta-casein (PubMed:10873535). Promotes apoptosis by either relieving the inhibition of BIRC proteins on caspases, leading to an increase in caspase activity; or by a BIRC inhibition-independent, caspase-independent and serine protease activity-dependent mechanism (PubMed:15200957). Cleaves BIRC6 and relieves its inhibition on CASP3, CASP7 and CASP9, but it is also prone to inhibition by BIRC6 (PubMed:36758104, PubM

Mitochondrion intermembrane spaceMitochondrion membraneEndoplasmic reticulum

3-methylglutaconic aciduria 8

An autosomal recessive inborn error of metabolism resulting in early death. Clinical features include extreme hypertonia observed at birth, alternating with hypotonia, subsequent appearance of extrapyramidal symptoms, lack of psychomotor development, microcephaly, and intractable seizures. Patients show lactic acidemia, 3-methylglutaconic aciduria, intermittent neutropenia, and progressive brain atrophy.

Facilitates the transport of serine from the cytosol to the mitochondria by interacting with and stabilizing Sideroflexin-1 (SFXN1), a mitochondrial serine transporter, playing a fundamental role in the one-carbon cycle responsible for the synthesis of nucleotides needed for mitochondrial DNA replication (PubMed:35235340). Plays an important role in the phosphatidylglycerol (PG) remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking (PubMed:2268371

Mitochondrion membraneEndoplasmic reticulumMitochondrion

3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome

An autosomal recessive disorder characterized by childhood onset of delayed psychomotor development or psychomotor regression, sensorineural deafness, spasticity or dystonia, and increased excretion of 3-methylglutaconic acid. Brain imaging shows cerebral and cerebellar atrophy as well as lesions in the basal ganglia reminiscent of Leigh syndrome. Laboratory studies show increased serum lactate and alanine, mitochondrial oxidative phosphorylation defects, abnormal mitochondria, abnormal phosphatidylglycerol and cardiolipin profiles in fibroblasts, and abnormal accumulation of unesterified cholesterol within cells.

May play some role in mitochondrial processes

Mitochondrion

3-methylglutaconic aciduria 3

An autosomal recessive metabolic disorder that causes a neuro-ophthalmologic syndrome consisting of early-onset bilateral optic atrophy, spasticity, extrapyramidal dysfunction and cognitive deficit. Urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid is increased. MGCA3 can be distinguished from MGCA1 by the absence of increase of 3-hydroxyisovaleric acid levels.

Transcription factor, which has both transcriptional activation and repression activities (PubMed:31905202). Also modulates chromatin accessibility (PubMed:38361031). In complex with HCFC1 and ZNF143, regulates the expression of several genes, including AP2S1, ESCO2, OPHN1, RBL1, UBXN8 and ZNF32 (PubMed:26416877). May regulate the expression of genes that encode both cytoplasmic and mitochondrial ribosomal proteins (By similarity). Required for normal mitochondrial development and function. Regu

NucleusCytoplasm

Methylmalonic aciduria and homocystinuria type cblL

An autosomal recessive disorder of cobalamin metabolism clinically characterized by early-onset seizures, and profound global developmental delay with severe intellectual disability. Metabolic features are mild methylmalonic aciduria, low-normal plasma methionine, and high-normal plasma homocysteine.

Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane (PubMed:25997101, PubMed:27623147, PubMed:32567732). Constituent of mature MICOS complex, it is required for the formation of cristae junction (CJ) and maintenance of cristae morphology (PubMed:25997101, PubMed:27623147, PubMed:32567732). Required for the incor

Mitochondrion inner membrane

Combined oxidative phosphorylation deficiency 37

An autosomal recessive disorder due to mitochondrial dysfunction and characterized by hypotonia, failure to thrive, progressive neurodegeneration with neurologic deterioration after the first months of life, global developmental delay, as well as liver dysfunction. Some patients may have hypertrophic cardiomyopathy, loss of vision and hearing, and/or seizures. Death in first months or years of life is observed in most patients.

Catalyzes the fifth step in the leucine degradation pathway, the reversible hydration of 3-methylglutaconyl-CoA (3-MG-CoA) to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) (PubMed:11738050, PubMed:12434311, PubMed:12655555, PubMed:16640564). Can catalyze the reverse reaction but at a much lower rate in vitro (PubMed:16640564). HMG-CoA is then quickly degraded by another enzyme (such as HMG-CoA lyase) to give acetyl-CoA and acetoacetate (PubMed:16640564). Uses other substrates such as (2E)-glutaconyl-

Mitochondrion

3-methylglutaconic aciduria 1

An inborn error of leucine metabolism. It leads to an autosomal recessive syndrome with variable clinical phenotype, ranging from delayed speech development to severe psychomotor retardation, coma, failure to thrive, metabolic acidosis and dystonia. MGCA1 can be distinguished from other forms of MGCA by the pattern of metabolite excretion: 3-methylglutaconic acid levels are higher than those detected in other forms, whereas methylglutaric acid levels are usually only slightly elevated and there is a high level of 3-hydroxyisovaleric acid excretion (not present in other MGCA forms).

Isobutyryl-CoA dehydrogenase which catalyzes the conversion of 2-methylpropanoyl-CoA to (2E)-2-methylpropenoyl-CoA in the valine catabolic pathway (PubMed:11013134, PubMed:12359132, PubMed:16857760). To a lesser extent, also able to catalyze the oxidation of (2S)-2-methylbutanoyl-CoA (PubMed:11013134, PubMed:12359132)

Mitochondrion

Isobutyryl-CoA dehydrogenase deficiency

An autosomal recessive metabolic disorder characterized by plasma carnitine deficiency and elevated C4-acylcarnitine. Patients manifest variable clinical features including failure to thrive, seizures, anemia, muscular hypotonia and developmental delay. Some patients may be asymptomatic.

Mitochondrial co-chaperone which forms a complex with prohibitins to regulate cardiolipin remodeling (By similarity). May be a component of the PAM complex, a complex required for the translocation of transit peptide-containing proteins from the inner membrane into the mitochondrial matrix in an ATP-dependent manner. May act as a co-chaperone that stimulate the ATP-dependent activity (By similarity)

Mitochondrion inner membrane

3-methylglutaconic aciduria 5

An autosomal recessive disorder characterized by early-onset dilated cardiomyopathy, growth failure, cerebellar ataxia causing significant motor delays, testicular dysgenesis, growth failure and significant increases in urine organic acids, particularly 3-methylglutaconic acid and 3-methylglutaric acid.

Membrane

A mitochondrial matrix enzyme that catalyzes the third step in leucine catabolism, where isovaleryl-CoA (3-methylbutanoyl-CoA) is metabolized to 3-methylbut-2-enoyl-CoA (PubMed:7640268). To a lesser extent, it also participates in the first step in fatty acid beta-oxidation, in which it catalyzes the proR-proR stereospecific alpha,beta-dehydrogenation of other saturated short-chain acyl-CoA thioesters such as pentanoyl-CoA, hexanoyl-CoA and butanoyl-CoA, using the electron transfer flavoprotein

Mitochondrion matrix

Isovaleric acidemia

A metabolic disorder characterized by retarded psychomotor development, a peculiar odor resembling sweaty feet, an aversion to dietary protein, and pernicious vomiting, leading to acidosis and coma. The acute neonatal form leads to massive metabolic acidosis from the first days of life and rapid death.

Catalyzes the initial reaction in intramitochondrial fatty acid synthesis, by activating malonate and methylmalonate, but not acetate, into their respective CoA thioester (PubMed:21841779, PubMed:21846720). May have some preference toward very-long-chain substrates (PubMed:17762044)

Mitochondrion

Combined malonic and methylmalonic aciduria

A metabolic disease characterized by malonic and methylmalonic aciduria, with urinary excretion of much larger amounts of methylmalonic acid than malonic acid, in the presence of normal malonyl-CoA decarboxylase activity. Clinical features include coma, ketoacidosis, hypoglycemia, failure to thrive, microcephaly, dystonia, axial hypotonia and/or developmental delay, and neurologic manifestations including seizures, psychiatric disease and/or cognitive decline.