BCKDHA

Last updated
BCKDHA
Protein BCKDHA PDB 1dtw.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases BCKDHA , BCKDE1A, MSU, MSUD1, OVD1A, branched chain keto acid dehydrogenase E1, alpha polypeptide, branched chain keto acid dehydrogenase E1 subunit alpha
External IDs OMIM: 608348; MGI: 107701; HomoloGene: 569; GeneCards: BCKDHA; OMA:BCKDHA - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001164783
NM_000709

NM_007533

RefSeq (protein)

NP_000700
NP_001158255

n/a

Location (UCSC) Chr 19: 41.4 – 41.43 Mb Chr 7: 25.33 – 25.36 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

A 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial is an enzyme that in humans is encoded by the BCKDHA gene. [5]

BCKDHA is a coding gene that is part of the BCKD complex (branched-chain alpha-keto acid dehydrogenase).

Discovery

BCKDHA was discovered by John Menkes in 1954. After he had seen a family with four children die only a few months after birth, he found that their urine smelled sweet like maple syrup. While he was not the one to discover the specific gene, he did discover the maple syrup urine disease [6] (MSUD). The BCKD complex is made up of three different catalytic pieces. It was in 1960 when Dancis discovered the gene itself, but this was from Menkes discovering of the disease leading to further investigation of its origin. He found that looking at the branched-chain amino acids and their corresponding alpha-keto acids in turn aided in the realization that they were pathogenetic compounds. Dancis was the one to specifically track down the enzymatic defect in (MSUD) by finding what gene in the pool of human chromosomes was defecting the urine. He found the gene on the level of the decarboxylation of the branched-chain amino acids. [7]

Gene location

The cytogenetic location of BCKDHA is on the human chromosome 19, specifically on the cytogenetic band at 19q13.2. This the long arm (q) of the chromosome 19 at 13.2. Looking at the molecular location, the base pairs 41,397,789 to 41,425,005 are on chromosome 19. The cellular localization of this gene is within the mitochondrion matrix. [8]

Function

The second major step in the catabolism of the branched-chain amino acids (isoleucine, leucine, and valine) is catalyzed by the branched-chain alpha-keto acid dehydrogenase complex (BCKD; EC 1.2.4.4), an inner-mitochondrial enzyme complex that consists of 3 catalytic components: a heterotetrameric (alpha2, beta2) branched-chain alpha-keto acid decarboxylase (E1), a homo-24-meric dihydrolipoyl transacylase (E2; MIM 248610), and a homodimeric dihydrolipoamide dehydrogenase (E3; MIM 238331). The reaction is irreversible and constitutes the first committed step in BCAA oxidation. The complex also contains 2 regulatory enzymes, a kinase and a phosphorylase. The BCKDHA gene encodes the alpha subunit of E1, and the BCKDHB gene (MIM 248611) encodes the beta subunit of E1.[supplied by OMIM] [5]

The normal function of the BCKDHA gene is to provide instructions for making the alpha subunit of the branched-chain alpha-keto dehydrogenase (BCKD) enzyme complex. The alpha subunit is one part of the BCKD enzyme complex. Two beta subunits are produced from the BCKDHB gene [9] and connect to two alpha subunits to form the E1 (decarboxylase) component. The BCKD enzyme complex catalyzes one step in breaking down amino acids. Those amino acids being leucine, isoleucine, and valine. The BCKD enzyme complex can be found in the mitochondria, an organelle known as the powerhouse of the cell. All three amino acids can be found in protein-rich foods and when broken down, they can be used for energy. Mutations in the BCKDHA gene can lead to maple syrup urine disease. [10]

Clinical significance

Mutations in the BCKDHA gene occur due to single point mutations in the “alpha subunit of the BCKD enzyme complex”. [6] Earlier cases of this disease show the mutation more frequently occurred by replacing the amino acid tyrosine. This amino acid was replaced with asparagine. The complication with mutations in the BCKDHA gene is that it disrupts the normal function of the BCKD enzyme complex, preventing the gene from going about its normal functions. Thus, the BCKDHA gene would not be able to break down leucine, isoleucine, and valine. When these byproducts start to accumulate it produces a toxic environment for cells and tissues, specifically in the nervous system. This can lead to seizures, developmental delay, but most importantly maple syrup urine disease.

The BCKDHA has been pinpointed in people with maple syrup urine disease, due to over 80 mutations occurring in that gene. Severe symptoms arise from these mutations and cause the disease which shows soon after birth. Due to the sweet odor from the urine, the disease was termed maple syrup urine disease. The disease causes loss of appetite, nausea, lethargy, and delayed development.

BCKDHA mutation: maple syrup urine disease

Maple syrup urine disease is an “autosomal recessive inborn error of metabolism. Meaning, as stated earlier, that there is a defect (i.e. error) in the single gene that codes for an enzyme. These enzymes promote conversions for various substrates into products. In terms of maple syrup urine disease, the enzyme defect occurs in the metabolic pathway of the “branched-chain amino acids” leucine, isoleucine, and valine. [9] The buildup of these amino acids lead to “encephalopathy and progressive neurodegeneration”; [9] along with other complications.

There are five forms of maple syrup urine disease: classic, intermediate, intermittent, thiamine-responsive and E3 deficient. The form of disease is dependent upon clinical prognosis, dietary protein tolerance, and thiamine response and level of enzyme activity. Intermediate maple syrup urine disease is a milder form of maple syrup urine disease because it persistently raises branched-chain amino acids and some keto-acid chains. Individuals with this disease have a partial BCKDHA enzyme deficiency. [6] Meaning that it shows up sporadically or reacts to dietary thiamine therapy.

Related Research Articles

<span class="mw-page-title-main">Isoleucine</span> Chemical compound

Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH+3 form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO form under biological conditions), and a hydrocarbon side chain with a branch (a central carbon atom bound to three other carbon atoms). It is classified as a non-polar, uncharged (at physiological pH), branched-chain, aliphatic amino acid. It is essential in humans, meaning the body cannot synthesize it. Essential amino acids are necessary in the human diet. In plants isoleucine can be synthesized from threonine and methionine. In plants and bacteria, isoleucine is synthesized from pyruvate employing leucine biosynthesis enzymes. It is encoded by the codons AUU, AUC, and AUA.

<span class="mw-page-title-main">Pyruvate dehydrogenase complex</span> Three-enzyme complex

Pyruvate dehydrogenase complex (PDC) is a complex of three enzymes that converts pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the citric acid cycle. Pyruvate decarboxylation is also known as the "pyruvate dehydrogenase reaction" because it also involves the oxidation of pyruvate.

<span class="mw-page-title-main">Maple syrup urine disease</span> Autosomal recessive metabolic disorder

Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder affecting branched-chain amino acids. It is one type of organic acidemia. The condition gets its name from the distinctive sweet odor of affected infants' urine and earwax, particularly prior to diagnosis and during times of acute illness. It was described by John Menkes in the 1950s.

<span class="mw-page-title-main">Branched-chain amino acid</span> Amino acid with a branched carbon chain

A branched-chain amino acid (BCAA) is an amino acid having an aliphatic side-chain with a branch. Among the proteinogenic amino acids, there are three BCAAs: leucine, isoleucine, and valine. Non-proteinogenic BCAAs include 2-aminoisobutyric acid and alloisoleucine.

The branched-chain α-ketoacid dehydrogenase complex is a multi-subunit complex of enzymes that is found on the mitochondrial inner membrane. This enzyme complex catalyzes the oxidative decarboxylation of branched, short-chain alpha-ketoacids. BCKDC is a member of the mitochondrial α-ketoacid dehydrogenase complex family, which also includes pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, key enzymes that function in the Krebs cycle.

Pyruvate dehydrogenase deficiency is a rare neurodegenerative disorder associated with abnormal mitochondrial metabolism. PDCD is a genetic disease resulting from mutations in one of the components of the pyruvate dehydrogenase complex (PDC). The PDC is a multi-enzyme complex that plays a vital role as a key regulatory step in the central pathways of energy metabolism in the mitochondria. The disorder shows heterogeneous characteristics in both clinical presentation and biochemical abnormality.

<span class="mw-page-title-main">Pyruvate dehydrogenase</span> Class of enzymes

Pyruvate dehydrogenase is an enzyme that catalyzes the reaction of pyruvate and a lipoamide to give the acetylated dihydrolipoamide and carbon dioxide. The conversion requires the coenzyme thiamine pyrophosphate.

<span class="mw-page-title-main">Dihydrolipoamide dehydrogenase</span> Protein-coding gene in the species Homo sapiens

Dihydrolipoamide dehydrogenase (DLD), also known as dihydrolipoyl dehydrogenase, mitochondrial, is an enzyme that in humans is encoded by the DLD gene. DLD is a flavoprotein enzyme that oxidizes dihydrolipoamide to lipoamide.

<span class="mw-page-title-main">E3 binding protein</span> Protein-coding gene in the species Homo sapiens

E3 binding protein also known as pyruvate dehydrogenase protein X component, mitochondrial is a protein that in humans is encoded by the PDHX gene. The E3 binding protein is a component of the pyruvate dehydrogenase complex found only in eukaryotes. Defects in this gene are a cause of pyruvate dehydrogenase deficiency which results in neurological dysfunction and lactic acidosis in infancy and early childhood. This protein is also a minor antigen for antimitochondrial antibodies. These autoantibodies are present in nearly 95% of patients with primary biliary cholangitis, an autoimmune disease of the liver. In primary biliary cholangitis, activated T lymphocytes attack and destroy epithelial cells in the bile duct where this protein is abnormally distributed and overexpressed. Primary biliary cholangitis eventually leads to liver failure.

<span class="mw-page-title-main">Pyruvate dehydrogenase (lipoamide) alpha 1</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial is an enzyme that in humans is encoded by the PDHA1 gene.The pyruvate dehydrogenase complex is a nuclear-encoded mitochondrial matrix multienzyme complex that provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the irreversible conversion of pyruvate into acetyl-CoA. The PDH complex is composed of multiple copies of 3 enzymes: E1 (PDHA1); dihydrolipoyl transacetylase (DLAT) ; and dihydrolipoyl dehydrogenase (DLD). The E1 enzyme is a heterotetramer of 2 alpha and 2 beta subunits. The E1-alpha subunit contains the E1 active site and plays a key role in the function of the PDH complex.

<span class="mw-page-title-main">Dihydrolipoyllysine-residue (2-methylpropanoyl)transferase</span>

In enzymology, a dihydrolipoyllysine-residue (2-methylpropanoyl)transferase (EC 2.3.1.168) is an enzyme that catalyzes the chemical reaction

In enzymology, a [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">DBT (gene)</span> Mammalian protein found in Homo sapiens

Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial is an enzyme that in humans is encoded by the DBT gene.

<span class="mw-page-title-main">DLST</span> Protein-coding gene in the species Homo sapiens

Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial is an enzyme that in humans is encoded by the DLST gene.

<span class="mw-page-title-main">BCKDHB</span> Protein-coding gene in the species Homo sapiens

2-Oxoisovalerate dehydrogenase subunit beta, mitochondrial is an enzyme that in humans is encoded by the BCKDHB gene.

<span class="mw-page-title-main">BCKDK</span> Protein-coding gene in the species Homo sapiens

Branched chain ketoacid dehydrogenase kinase (BCKDK) is an enzyme encoded by the BCKDK gene on chromosome 16. This enzyme is part of the mitochondrial protein kinases family and it is a regulator of the valine, leucine, and isoleucine catabolic pathways. BCKDK is found in the mitochondrial matrix and the prevalence of it depends on the type of cell. Liver cells tend to have the lowest concentration of BCKDK, whereas skeletal muscle cells have the highest amount. Abnormal activity of this enzyme often leads to diseases such as maple syrup urine disease and cachexia.

<span class="mw-page-title-main">Alpha-aminoadipic semialdehyde synthase</span> Protein-coding gene in the species Homo sapiens

Alpha-aminoadipic semialdehyde synthase is an enzyme encoded by the AASS gene in humans and is involved in their major lysine degradation pathway. It is similar to the separate enzymes coded for by the LYS1 and LYS9 genes in yeast, and related to, although not similar in structure, the bifunctional enzyme found in plants. In humans, mutations in the AASS gene, and the corresponding alpha-aminoadipic semialdehyde synthase enzyme are associated with familial hyperlysinemia. This rare disease is inherited in an autosomal recessive pattern and patients often have no clinical symptoms.

α-Ketoisocaproic acid Chemical compound

α-Ketoisocaproic acid (α-KIC), also known as 4-methyl-2-oxovaleric acid, and its conjugate base and carboxylate, α-ketoisocaproate, are metabolic intermediates in the metabolic pathway for L-leucine. Leucine is an essential amino acid, and its degradation is critical for many biological duties. α-KIC is produced in one of the first steps of the pathway by branched-chain amino acid aminotransferase by transferring the amine on L-leucine onto alpha ketoglutarate, and replacing that amine with a ketone. The degradation of L-leucine in the muscle to this compound allows for the production of the amino acids alanine and glutamate as well. In the liver, α-KIC can be converted to a vast number of compounds depending on the enzymes and cofactors present, including cholesterol, acetyl-CoA, isovaleryl-CoA, and other biological molecules. Isovaleryl-CoA is the main compound synthesized from ɑ-KIC. α-KIC is a key metabolite present in the urine of people with Maple syrup urine disease, along with other branched-chain amino acids. Derivatives of α-KIC have been studied in humans for their ability to improve physical performance during anaerobic exercise as a supplemental bridge between short-term and long-term exercise supplements. These studies show that α-KIC does not achieve this goal without other ergogenicsupplements present as well. α-KIC has also been observed to reduce skeletal muscle damage after eccentrically biased resistance exercises in people who do not usually perform those exercises.

<span class="mw-page-title-main">Pyruvate dehydrogenase (lipoamide) beta</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase (lipoamide) beta, also known as pyruvate dehydrogenase E1 component subunit beta, mitochondrial or PDHE1-B is an enzyme that in humans is encoded by the PDHB gene. The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO2, and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 beta subunit. Mutations in this gene are associated with pyruvate dehydrogenase E1-beta deficiency.

<span class="mw-page-title-main">NDUFA11</span> Protein and coding gene in humans

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 is an enzyme that in humans is encoded by the NDUFA11 gene. The NDUFA11 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain Mutations in subunits of NADH dehydrogenase (ubiquinone), also known as Complex I, frequently lead to complex neurodegenerative diseases such as Leigh's syndrome. Mutations in this gene are associated with severe mitochondrial complex I deficiency.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000248098 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000060376 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 "Entrez Gene: BCKDHA branched chain keto acid dehydrogenase E1, alpha polypeptide".
  6. 1 2 3 Reference, Genetics Home. "BCKDHA gene". Genetics Home Reference. Retrieved 2018-11-14.
  7. Reference, Genetics Home. "BCKDHA gene". Genetics Home Reference. Retrieved 2018-11-15.
  8. "BCKDHA branched chain keto acid dehydrogenase E1, alpha polypeptide". NCBI. Retrieved 12 April 2019.
  9. 1 2 3 Database, GeneCards Human Gene. "BCKDHA Gene - GeneCards | ODBA Protein | ODBA Antibody". www.genecards.org. Retrieved 2018-11-14.
  10. Database, GeneCards Human Gene. "BCKDHA Gene - GeneCards | ODBA Protein | ODBA Antibody". www.genecards.org. Retrieved 2018-11-15.

Further reading