BCKDK

Last updated
BCKDK
Protein BCKDK PDB 1gjv.png
Identifiers
Aliases BCKDK , BCKDKD, BDK, branched chain ketoacid dehydrogenase kinase, branched chain keto acid dehydrogenase kinase
External IDs OMIM: 614901 MGI: 1276121 HomoloGene: 37642 GeneCards: BCKDK
Orthologs
SpeciesHumanMouse
Entrez

10295

12041

Ensembl

ENSG00000103507

ENSMUSG00000030802

UniProt

O14874

O55028

RefSeq (mRNA)

NM_005881
NM_001122957
NM_001271926

NM_009739

RefSeq (protein)

NP_001116429
NP_001258855
NP_005872
NP_005872.2

NP_033869

Location (UCSC) Chr 16: 31.11 – 31.11 Mb Chr 7: 127.5 – 127.51 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] 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. [6] [7] Abnormal activity of this enzyme often leads to diseases such as maple syrup urine disease and cachexia.

Contents

Structure

BCKDK's structure consists of a characteristic nucleotide-binding domain along with a four-helix bundle domain similar to certain aspects of protein histidine kinases, which are involved in two-component signal transduction systems. BCKDK is also a dimer with a Leu389 residue located between the dimers and this dimerization is seen to be essential for its kinase activity and protein stability. [8] Moreover, it is made up of 382 amino acids and has a molecular weight of 43 kDa. [6] The gene BCKDK is located at 16p11.2, has an exon count of 11, and it lacks a TATA-box and an initiator element. [5] [7]

Function

BCKDK regulates the activity of branched-chain α-ketoacid dehydrogenase complex (BCKD) through phosphorylation and inactivation. This inactivation results in increased branched-chain amino acids (BCAA), which is seen to reduce oxidative stress; however, having too much BCAA has been proven to be toxic to humans. Therefore, BCKDK is a vital tool to assist with BCAA homeostasis. [9] [10] As stated earlier, BCKDK concentrations vary depending on the type of tissue that is observed, whereas BCKD's concentration is the same in any tissue. Although BCKD concentration is constant, the amount of BCKDK determines the activity of the dehydrogenase complex. Since liver tissue is seen to have the lowest concentration of BCKDK, the activity of BCKD is seen to be the highest, delineating the fact that the BCKD kinase inversely affects the BCKD activity. [7]

Clinical significance

Abnormalities in BCKD activity often leads to pathological conditions which is why BCKDK is needed to regulate it. Often, mutations in the BCKDK gene occur creating the deviation in BCKD behavior. Exceedingly high BCKD complex activity increases branched-chain amino acid catabolism and protein degradation in skeletal muscle, which is a distinctive feature for cachexia. Deficiencies in BCKD activity have been the main cause in the rare metabolism maple syrup urine disease that can lead to mental retardation, brain edema, seizures, coma, and death if not treated correctly by lifelong limitation of branched-chain amino acid intake. [7] Because BCKDK regulates BCKD which in turn catalyzes BCAA, BCKDK is one of the factors that determines the concentration of BCAA levels. High BCAA levels can lead to insulin resistance and can be a potential marker for type 2 diabetes. [10] The amalgamation of BCAA can also lead to congenital heart diseases and heart failure. Furthermore, low levels of BCAA have been described as a cause of comorbid intellectual disability, autism, and epilepsy. [8]

Deficiency of BCKDK, first described in 2012, [11] is a disorder that could be considered as the "opposite" of maple syrup disease, because patients have decreased levels of branched-chain amino acids, instead of increased levels. The condition may present as autism with epileptiform abnormalities on EEG and seizures.

Interactions

BCKDK has been seen to interact with:

Related Research Articles

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

Pyruvate dehydrogenase lipoamide kinase isozyme 1, mitochondrial is an enzyme that in humans is encoded by the PDK1 gene. It codes for an isozyme of pyruvate dehydrogenase kinase (PDK).

<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.

<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 phosphatase</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase phosphatase catalytic subunit 1, also known as protein phosphatase 2C, is an enzyme that in humans is encoded by the PDP1 gene. PDPC 1 is an enzyme which serves to reverse the effects of pyruvate dehydrogenase kinase upon pyruvate dehydrogenase, activating pyruvate dehydrogenase.

<span class="mw-page-title-main">Branched-chain amino acid aminotransferase</span> Aminotransferase enzyme

Branched-chain amino acid aminotransferase (BCAT), also known as branched-chain amino acid transaminase, is an aminotransferase enzyme (EC 2.6.1.42) which acts upon branched-chain amino acids (BCAAs). It is encoded by the BCAT2 gene in humans. The BCAT enzyme catalyzes the conversion of BCAAs and α-ketoglutarate into branched chain α-keto acids and glutamate.

<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.

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

<span class="mw-page-title-main">PDK4</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase lipoamide kinase isozyme 4, mitochondrial (PDK4) is an enzyme that in humans is encoded by the PDK4 gene. It codes for an isozyme of pyruvate dehydrogenase kinase.

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

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

<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">PDK2</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase kinase isoform 2 (PDK2) also known as pyruvate dehydrogenase lipoamide kinase isozyme 2, mitochondrial is an enzyme that in humans is encoded by the PDK2 gene. PDK2 is an isozyme of pyruvate dehydrogenase kinase.

<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">IDH3A</span> Protein-coding gene in the species Homo sapiens

Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial (IDH3α) is an enzyme that in humans is encoded by the IDH3A gene.

<span class="mw-page-title-main">PDK3</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase lipoamide kinase isozyme 3, mitochondrial is an enzyme that in humans is encoded by the PDK3 gene. It codes for an isozyme of pyruvate dehydrogenase kinase.The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO2. It provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle, and thus is one of the major enzymes responsible for the regulation of glucose metabolism. The enzymatic activity of PDH is regulated by a phosphorylation/dephosphorylation cycle, and phosphorylation results in inactivation of PDH. The protein encoded by this gene is one of the four pyruvate dehydrogenase kinases that inhibits the PDH complex by phosphorylation of the E1 alpha subunit. This gene is predominantly expressed in the heart and skeletal muscles. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

<span class="mw-page-title-main">IDH3G</span> Protein-coding gene in the species Homo sapiens

Isocitrate dehydrogenase [NAD] subunit gamma, mitochondrial is an enzyme that in humans is encoded by the IDH3G gene.

<span class="mw-page-title-main">IDH3B</span> Protein-coding gene in the species Homo sapiens

Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial is an enzyme that in humans is encoded by the IDH3B gene.

<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">Acyl-CoA thioesterase 9</span> Protein-coding gene in humans

Acyl-CoA thioesterase 9 is a protein that is encoded by the human ACOT9 gene. It is a member of the acyl-CoA thioesterase superfamily, which is a group of enzymes that hydrolyze Coenzyme A esters. There is no known function, however it has been shown to act as a long-chain thioesterase at low concentrations, and a short-chain thioesterase at high concentrations.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000103507 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000030802 - 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: BCKDK branched chain ketoacid dehydrogenase kinase".
  6. 1 2 3 Popov KM, Zhao Y, Shimomura Y, Kuntz MJ, Harris RA (Jul 1992). "Branched-chain alpha-ketoacid dehydrogenase kinase. Molecular cloning, expression, and sequence similarity with histidine protein kinases". The Journal of Biological Chemistry. 267 (19): 13127–30. doi: 10.1016/S0021-9258(18)42179-5 . PMID   1377677.
  7. 1 2 3 4 Muller EA, Danner DJ (Oct 2004). "Tissue-specific translation of murine branched-chain alpha-ketoacid dehydrogenase kinase mRNA is dependent upon an upstream open reading frame in the 5'-untranslated region". The Journal of Biological Chemistry. 279 (43): 44645–55. doi: 10.1074/jbc.M406550200 . PMID   15302860.
  8. 1 2 García-Cazorla A, Oyarzabal A, Fort J, Robles C, Castejón E, Ruiz-Sala P, Bodoy S, Merinero B, Lopez-Sala A, Dopazo J, Nunes V, Ugarte M, Artuch R, Palacín M, Rodríguez-Pombo P, Alcaide P, Navarrete R, Sanz P, Font-Llitjós M, Vilaseca MA, Ormaizabal A, Pristoupilova A, Agulló SB (Apr 2014). "Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients". Human Mutation. 35 (4): 470–7. doi: 10.1002/humu.22513 . PMID   24449431. S2CID   205922143.
  9. ↑ Tso SC, Gui WJ, Wu CY, Chuang JL, Qi X, Skvora KJ, Dork K, Wallace AL, Morlock LK, Lee BH, Hutson SM, Strom SC, Williams NS, Tambar UK, Wynn RM, Chuang DT (Jul 2014). "Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain α-ketoacid dehydrogenase kinase". The Journal of Biological Chemistry. 289 (30): 20583–93. doi: 10.1074/jbc.M114.569251 . PMC   4110271 . PMID   24895126.
  10. 1 2 Tso SC, Qi X, Gui WJ, Chuang JL, Morlock LK, Wallace AL, Ahmed K, Laxman S, Campeau PM, Lee BH, Hutson SM, Tu BP, Williams NS, Tambar UK, Wynn RM, Chuang DT (Jun 2013). "Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase". Proceedings of the National Academy of Sciences of the United States of America. 110 (24): 9728–33. Bibcode:2013PNAS..110.9728T. doi: 10.1073/pnas.1303220110 . PMC   3683707 . PMID   23716694.
  11. ↑ Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM, Schroth J, Silhavy JL, Kara M, Khalil RO, Ben-Omran T, Ercan-Sencicek AG, Hashish AF, Sanders SJ, Gupta AR, Hashem HS, Matern D, Gabriel S, Sweetman L, Rahimi Y, Harris RA, State MW, Gleeson JG (October 2012). "Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy". Science. 338 (6105): 394–7. Bibcode:2012Sci...338..394N. doi:10.1126/science.1224631. PMC   3704165 . PMID   22956686.

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