UniProt functional annotation for P07954



	UniProt functional annotation for P07954

UniProt code: P07954.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Catalyzes the reversible stereospecific interconversion of fumarate to L-malate (PubMed:30761759). Experiments in other species have demonstrated that specific isoforms of this protein act in defined pathways and favor one direction over the other (Probable). {ECO:0000269|PubMed:30761759, ECO:0000305}.

Function: [Isoform Mitochondrial]: Catalyzes the hydration of fumarate to L-malate in the tricarboxylic acid (TCA) cycle to facilitate a transition step in the production of energy in the form of NADH. {ECO:0000250|UniProtKB:P10173}.

Function: [Isoform Cytoplasmic]: Catalyzes the dehydration of L-malate to fumarate (By similarity). Fumarate metabolism in the cytosol plays a role during urea cycle and arginine metabolism; fumarate being a by- product of the urea cycle and amino-acid catabolism (By similarity). Also plays a role in DNA repair by promoting non-homologous end-joining (NHEJ) (PubMed:20231875, PubMed:26237645). In response to DNA damage and phosphorylation by PRKDC, translocates to the nucleus and accumulates at DNA double-strand breaks (DSBs): acts by catalyzing formation of fumarate, an inhibitor of KDM2B histone demethylase activity, resulting in enhanced dimethylation of histone H3 'Lys-36' (H3K36me2) (PubMed:26237645). {ECO:0000250|UniProtKB:P97807, ECO:0000269|PubMed:20231875, ECO:0000269|PubMed:26237645}.

Catalytic activity: Reaction=(S)-malate = fumarate + H2O; Xref=Rhea:RHEA:12460, ChEBI:CHEBI:15377, ChEBI:CHEBI:15589, ChEBI:CHEBI:29806; EC=4.2.1.2; Evidence={ECO:0000269|PubMed:30761759, ECO:0000305|PubMed:30718813};

Catalytic activity: [Isoform Mitochondrial]: Reaction=(S)-malate = fumarate + H2O; Xref=Rhea:RHEA:12460, ChEBI:CHEBI:15377, ChEBI:CHEBI:15589, ChEBI:CHEBI:29806; EC=4.2.1.2; Evidence={ECO:0000250|UniProtKB:P10173}; PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:12462; Evidence={ECO:0000250|UniProtKB:P10173};

Catalytic activity: [Isoform Cytoplasmic]: Reaction=(S)-malate = fumarate + H2O; Xref=Rhea:RHEA:12460, ChEBI:CHEBI:15377, ChEBI:CHEBI:15589, ChEBI:CHEBI:29806; EC=4.2.1.2; Evidence={ECO:0000250|UniProtKB:P97807}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12461; Evidence={ECO:0000250|UniProtKB:P97807};

Biophysicochemical properties: Kinetic parameters: KM=1.4 mM for L-malate (at pH 8.5) {ECO:0000269|PubMed:30761759}; KM=0.2 mM for fumarate (at pH 8.5) {ECO:0000269|PubMed:30761759}; Note=Kcat is 280 sec(-1) with L-malate (at pH 8.5) (PubMed:30761759). Kcat is 170 sec(-1) with fumarate (at pH 8.5) (PubMed:30761759). {ECO:0000269|PubMed:30761759}; pH dependence: Optimum pH is 7.5-8.0. {ECO:0000269|PubMed:30761759};

Pathway: Carbohydrate metabolism; tricarboxylic acid cycle; (S)-malate from fumarate: step 1/1. {ECO:0000250|UniProtKB:P10173}.

Subunit: Homotetramer (PubMed:21445611, PubMed:30761759). Interacts with H2AZ1 (PubMed:26237645). {ECO:0000269|PubMed:21445611, ECO:0000269|PubMed:26237645, ECO:0000269|PubMed:30761759}.

Subcellular location: [Isoform Mitochondrial]: Mitochondrion {ECO:0000269|PubMed:27037871}.

Subcellular location: [Isoform Cytoplasmic]: Cytoplasm, cytosol {ECO:0000269|PubMed:20231875, ECO:0000269|PubMed:22509282, ECO:0000269|PubMed:26237645, ECO:0000269|PubMed:27037871}. Nucleus {ECO:0000269|PubMed:20231875, ECO:0000269|PubMed:26237645}. Chromosome {ECO:0000269|PubMed:26237645}. Note=Translocates to the nucleus in response to DNA damage: localizes to DNA double-strand breaks (DSBs) following phosphorylation by PRKDC. {ECO:0000269|PubMed:26237645}.

Tissue specificity: Expressed in red blood cells; underexpressed in red blood cells (cytoplasm) of patients with hereditary non-spherocytic hemolytic anemia of unknown etiology. {ECO:0000269|PubMed:22509282}.

Ptm: [Isoform Cytoplasmic]: Phosphorylation at Thr-236 by PRKDC in response to DNA damage promotes translocation to the nucleus and recruitment to DNA double-strand breaks (DSBs). {ECO:0000269|PubMed:26237645}.

Disease: Fumarase deficiency (FMRD) [MIM:606812]: A severe autosomal recessive metabolic disorder characterized by early-onset hypotonia, profound psychomotor retardation, and brain abnormalities, such as agenesis of the corpus callosum, gyral defects, and ventriculomegaly. Many patients show neonatal distress, metabolic acidosis, and/or encephalopathy. {ECO:0000269|PubMed:9635293, ECO:0000269|Ref.23}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: [Isoform Cytoplasmic]: Hereditary leiomyomatosis and renal cell cancer (HLRCC) [MIM:150800]: A disorder characterized by predisposition to cutaneous and uterine leiomyomas, and papillary type 2 renal cancer which occurs in about 20% of patients. {ECO:0000269|PubMed:11865300, ECO:0000269|PubMed:26237645, ECO:0000269|PubMed:8200987}. Note=The disease is caused by variants affecting the gene represented in this entry. Isoform Cytoplasmic: HLRCC is probably caused by an accumulation of fumarate (PubMed:30718813). Accumulation of fumarate coupled with protonation promotes the formation of non-enzymatic post-translational modification cysteine S-succination (S-(2-succinyl)cysteine) on proteins, such as SMARCC1 (PubMed:30718813). {ECO:0000269|PubMed:30718813}.

Miscellaneous: There are 2 substrate-binding sites: the catalytic A site, and the non-catalytic B site that may play a role in the transfer of substrate or product between the active site and the solvent. Alternatively, the B site may bind allosteric effectors. {ECO:0000250|UniProtKB:P05042, ECO:0000250|UniProtKB:P9WN93}.

Similarity: Belongs to the class-II fumarase/aspartase family. Fumarase subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Catalyzes the reversible stereospecific interconversion of fumarate to L-malate (PubMed:30761759). Experiments in other species have demonstrated that specific isoforms of this protein act in defined pathways and favor one direction over the other (Probable). {ECO:0000269\|PubMed:30761759, ECO:0000305}.



Function:		[Isoform Mitochondrial]: Catalyzes the hydration of fumarate to L-malate in the tricarboxylic acid (TCA) cycle to facilitate a transition step in the production of energy in the form of NADH. {ECO:0000250\|UniProtKB:P10173}.



Function:		[Isoform Cytoplasmic]: Catalyzes the dehydration of L-malate to fumarate (By similarity). Fumarate metabolism in the cytosol plays a role during urea cycle and arginine metabolism; fumarate being a by- product of the urea cycle and amino-acid catabolism (By similarity). Also plays a role in DNA repair by promoting non-homologous end-joining (NHEJ) (PubMed:20231875, PubMed:26237645). In response to DNA damage and phosphorylation by PRKDC, translocates to the nucleus and accumulates at DNA double-strand breaks (DSBs): acts by catalyzing formation of fumarate, an inhibitor of KDM2B histone demethylase activity, resulting in enhanced dimethylation of histone H3 'Lys-36' (H3K36me2) (PubMed:26237645). {ECO:0000250\|UniProtKB:P97807, ECO:0000269\|PubMed:20231875, ECO:0000269\|PubMed:26237645}.


Catalytic activity:		Reaction=(S)-malate = fumarate + H2O; Xref=Rhea:RHEA:12460, ChEBI:CHEBI:15377, ChEBI:CHEBI:15589, ChEBI:CHEBI:29806; EC=4.2.1.2; Evidence={ECO:0000269\|PubMed:30761759, ECO:0000305\|PubMed:30718813};
Catalytic activity:		[Isoform Mitochondrial]: Reaction=(S)-malate = fumarate + H2O; Xref=Rhea:RHEA:12460, ChEBI:CHEBI:15377, ChEBI:CHEBI:15589, ChEBI:CHEBI:29806; EC=4.2.1.2; Evidence={ECO:0000250\|UniProtKB:P10173}; PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:12462; Evidence={ECO:0000250\|UniProtKB:P10173};
Catalytic activity:		[Isoform Cytoplasmic]: Reaction=(S)-malate = fumarate + H2O; Xref=Rhea:RHEA:12460, ChEBI:CHEBI:15377, ChEBI:CHEBI:15589, ChEBI:CHEBI:29806; EC=4.2.1.2; Evidence={ECO:0000250\|UniProtKB:P97807}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12461; Evidence={ECO:0000250\|UniProtKB:P97807};
Biophysicochemical properties:		Kinetic parameters: KM=1.4 mM for L-malate (at pH 8.5) {ECO:0000269\|PubMed:30761759}; KM=0.2 mM for fumarate (at pH 8.5) {ECO:0000269\|PubMed:30761759}; Note=Kcat is 280 sec(-1) with L-malate (at pH 8.5) (PubMed:30761759). Kcat is 170 sec(-1) with fumarate (at pH 8.5) (PubMed:30761759). {ECO:0000269\|PubMed:30761759}; pH dependence: Optimum pH is 7.5-8.0. {ECO:0000269\|PubMed:30761759};
Pathway:		Carbohydrate metabolism; tricarboxylic acid cycle; (S)-malate from fumarate: step 1/1. {ECO:0000250\|UniProtKB:P10173}.
Subunit:		Homotetramer (PubMed:21445611, PubMed:30761759). Interacts with H2AZ1 (PubMed:26237645). {ECO:0000269\|PubMed:21445611, ECO:0000269\|PubMed:26237645, ECO:0000269\|PubMed:30761759}.
Subcellular location:		[Isoform Mitochondrial]: Mitochondrion {ECO:0000269\|PubMed:27037871}.
Subcellular location:		[Isoform Cytoplasmic]: Cytoplasm, cytosol {ECO:0000269\|PubMed:20231875, ECO:0000269\|PubMed:22509282, ECO:0000269\|PubMed:26237645, ECO:0000269\|PubMed:27037871}. Nucleus {ECO:0000269\|PubMed:20231875, ECO:0000269\|PubMed:26237645}. Chromosome {ECO:0000269\|PubMed:26237645}. Note=Translocates to the nucleus in response to DNA damage: localizes to DNA double-strand breaks (DSBs) following phosphorylation by PRKDC. {ECO:0000269\|PubMed:26237645}.
Tissue specificity:		Expressed in red blood cells; underexpressed in red blood cells (cytoplasm) of patients with hereditary non-spherocytic hemolytic anemia of unknown etiology. {ECO:0000269\|PubMed:22509282}.
Ptm:		[Isoform Cytoplasmic]: Phosphorylation at Thr-236 by PRKDC in response to DNA damage promotes translocation to the nucleus and recruitment to DNA double-strand breaks (DSBs). {ECO:0000269\|PubMed:26237645}.
Disease:		Fumarase deficiency (FMRD) [MIM:606812]: A severe autosomal recessive metabolic disorder characterized by early-onset hypotonia, profound psychomotor retardation, and brain abnormalities, such as agenesis of the corpus callosum, gyral defects, and ventriculomegaly. Many patients show neonatal distress, metabolic acidosis, and/or encephalopathy. {ECO:0000269\|PubMed:9635293, ECO:0000269\|Ref.23}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		[Isoform Cytoplasmic]: Hereditary leiomyomatosis and renal cell cancer (HLRCC) [MIM:150800]: A disorder characterized by predisposition to cutaneous and uterine leiomyomas, and papillary type 2 renal cancer which occurs in about 20% of patients. {ECO:0000269\|PubMed:11865300, ECO:0000269\|PubMed:26237645, ECO:0000269\|PubMed:8200987}. Note=The disease is caused by variants affecting the gene represented in this entry. Isoform Cytoplasmic: HLRCC is probably caused by an accumulation of fumarate (PubMed:30718813). Accumulation of fumarate coupled with protonation promotes the formation of non-enzymatic post-translational modification cysteine S-succination (S-(2-succinyl)cysteine) on proteins, such as SMARCC1 (PubMed:30718813). {ECO:0000269\|PubMed:30718813}.
Miscellaneous:		There are 2 substrate-binding sites: the catalytic A site, and the non-catalytic B site that may play a role in the transfer of substrate or product between the active site and the solvent. Alternatively, the B site may bind allosteric effectors. {ECO:0000250\|UniProtKB:P05042, ECO:0000250\|UniProtKB:P9WN93}.
Similarity:		Belongs to the class-II fumarase/aspartase family. Fumarase subfamily. {ECO:0000305}.