Pyruvate dehydrogenase (lipoamide) beta

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

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.[1][2] 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.[1]

## Contents

* 1 Structure
* 2 Function
* 3 Clinical significance
* 4 Interactive pathway map
* 5 References
* 6 Further reading

## Structure

The PDH genes that comprise the E1 subunit are 1.36 kilobases long (alpha) and 1.69 kb long (beta).[3] The PDHB gene has a total of 10 exons and 9 introns. All intron-exon splice junctions follow the standard GT/AG rule. There was an Alu family found in introns 2 and 8. The 5' flanking region gene contains a "CAAT" consensus promoter sequence but no "TATA" sequence. The transcription start site is an adenine residue located 132 bases upstream from the initiation codon in exon 1.[4] The mRNA species that results from transcription of PDHB has been experimentally determined, via Northern blotting, to be 1.6 kb in length, although another fragment 5.5 kb long was also identified.[5]

The PDHB gene encodes a precursor protein that has 359 amino acid residues and a final mature protein that has 329 amino acids, and is part of the pyruvate dehydrogenase multienzyme complex.[3] Two of the mature PDHB proteins come together with two PDHA proteins to form a heterotetrameric E1 subunit. Crystal Structures allowed for a model in which the enzyme undergoes a 2-A shuttle-like motion of its heterodimers to perform the catalysis.[6] Specifically, the catalytic residue has been identified on the PDHB subunit, the 89th residue, which is a glutamate.[7] In forming the entire PDH complex, the 289th beta residue, aspartic acid, interacts with the 276th residue of the E2 complex, a lysine.[8] The entire human complex is 9.5 MDa in size, and has been described as 60-meric, meaning there are over 60 components that are assembled to make the entire complex. These subunits are conserved across many species, as the function of this complex is essential for the generation of ATP for all eukaryotes.[9] Each component is responsible for the catalysis of one step in this pathway; this complex exists for the purpose of channeling the intermediates of each reaction to the next enzyme, thus greatly increasing the rate of reaction.[10]

## Function

The pyruvate dehydrogenase complex is responsible for the oxidative decarboxylation of pyruvate, with the final product being Acetyl CoA. Overall the complex catalyzes five reactions, with the overall reaction being:

Pyruvate + CoA \+ NAD+ → acetyl-CoA + CO2

There are three different coenzymes required throughout the 5 steps that this complex carries out: thiamine pyrophosphate (TPP), lipoamide, and coenzyme A. This step is only one of the central metabolic pathway carried out by eukaryotes, in which glucose is oxidized to form carbon dioxide, water, and ATP. The E1 complex specifically uses the TPP cofactor to cleave the Calpha-C(=O) bond of pyruvate, and then transfer the acetyl group to the TPP coenzyme, thus resulting in an intermediate, hydroxylethyl-Tpp*E1, and producing CO2. The thiazolium ring on the TPP is ideal for adding to carbonyl groups and acting as an electron sink, or a group that can pull electrons from a reaction and stabilize an electron-deficient intermediate.[10] Additionally, PDHB interacts with Prolyl-hydroxylase PHD3 to regulate the cellular PDH activity.[11]

## Clinical significance

Mutations in the PDHB gene have been known to cause one form of pyruvate dehydrogenase deficiency. Pyruvate dehydrogenase deficiency is characterized by the buildup of a chemical called lactic acid in the body and a variety of neurological problems. Signs and symptoms of this condition usually first appear shortly after birth, and they can vary widely among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. Most have delayed development of mental abilities and motor skills such as sitting and walking. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking. Some affected individuals have abnormal brain structures, such as underdevelopment of the tissue connecting the left and right halves of the brain (corpus callosum), wasting away (atrophy) of the exterior part of the brain known as the cerebral cortex, or patches of damaged tissue (lesions) on some parts of the brain. Because of the severe health effects, many individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood.[1] Most cases of pyruvate dehydrogenase complex (PDHc) deficiency are attributable to mutations in the PDHA1 gene which encodes the E(1)α subunit, with few cases of mutations in the genes for E3, E3BP, and E2 being described. However, there are a few cases in which mutations in the beta subunit gene have resulted in patients with Leigh syndrome.[12] Many pathological mutations have been described, including: R36C, which results in conformational change due to increased amino acid interactions; C306R, overall affecting interaction of the two beta subunits; I142M, affecting conformation around a potassium ion, thereby reducing PDHB stability; W165S, which also affects hydrophobic interaction between the beta subunits; and Y132C.[13] Other cases have been described in which there are no pathological mutations, but inborn errors of metabolism, specifically related to ubiquitination and proteasome machineries, resulted in a PDHB deficiency. This was demonstrated by PDH activity being restored in cells that were treated with MG132, which is known as proteasome inhibitor.[14] The clinical manifestations of this deficiency are similar to those of PDHA1 deficiency, with the exception being that ataxia is less frequent in these cases, and that consanguinity was found only in families with the PDHB deficiency.[13]

## Interactive pathway map

## References

1. ↑ 1.0 1.1 1.2 "Entrez Gene: pyruvate dehydrogenase (lipoamide) beta". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5162.
2. ↑ "Molecular cloning and characterization of human pyruvate dehydrogenase beta subunit gene". Proceedings of the National Academy of Sciences of the United States of America 87 (15): 5594–7. Aug 1990. doi:10.1073/pnas.87.15.5594. PMID 2377599. Bibcode: 1990PNAS...87.5594K.
3. ↑ 3.0 3.1 "Cloning and sequencing of cDNAs encoding alpha and beta subunits of human pyruvate dehydrogenase". Proceedings of the National Academy of Sciences of the United States of America 85 (1): 41–5. Jan 1988. doi:10.1073/pnas.85.1.41. PMID 3422424. Bibcode: 1988PNAS...85...41K.
4. ↑ "Molecular cloning and characterization of human pyruvate dehydrogenase beta subunit gene". Proceedings of the National Academy of Sciences of the United States of America 87 (15): 5594–7. Aug 1990. doi:10.1073/pnas.87.15.5594. PMID 2377599. Bibcode: 1990PNAS...87.5594K.
5. ↑ "Isolation, characterization and chromosomal localization of cDNA clones for the E1 beta subunit of the pyruvate dehydrogenase complex". European Journal of Biochemistry 194 (2): 587–92. Dec 1990. doi:10.1111/j.1432-1033.1990.tb15656.x. PMID 1702713.
6. ↑ "Structural basis for flip-flop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase". The Journal of Biological Chemistry 278 (23): 21240–6. Jun 2003. doi:10.1074/jbc.M300339200. PMID 12651851.
7. ↑ "Identification of the catalytic glutamate in the E1 component of human pyruvate dehydrogenase". FEBS Letters 437 (3): 273–7. Oct 1998. doi:10.1016/s0014-5793(98)01249-6. PMID 9824306.
8. ↑ "Binding of pyruvate dehydrogenase to the core of the human pyruvate dehydrogenase complex". FEBS Letters 582 (3): 468–72. Feb 2008. doi:10.1016/j.febslet.2007.12.041. PMID 18206651.
9. ↑ "Organization of the cores of the mammalian pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and their capacities to bind the E1 and E3 components". The Journal of Biological Chemistry 279 (8): 6921–33. Feb 2004. doi:10.1074/jbc.M308172200. PMID 14638692.
10. ↑ 10.0 10.1 Voet, Donald J.; Voet, Judith G.; Pratt, Charlotte W. (2010). "Chapter 17, Citric Acid Cycle". Principles of Biochemistry (4th ed.). Wiley. p. 550. ISBN 978-0-470-23396-2.
11. ↑ "Prolyl-hydroxylase PHD3 interacts with pyruvate dehydrogenase (PDH)-E1β and regulates the cellular PDH activity". Biochemical and Biophysical Research Communications 451 (2): 288–94. Aug 2014. doi:10.1016/j.bbrc.2014.07.114. PMID 25088999.
12. ↑ "PDH E1β deficiency with novel mutations in two patients with Leigh syndrome". Journal of Inherited Metabolic Disease 32 (Suppl 1): S339–43. Dec 2009. doi:10.1007/s10545-009-1343-1. PMID 19924563.
13. ↑ 13.0 13.1 "Mutations of the E1beta subunit gene (PDHB) in four families with pyruvate dehydrogenase deficiency". Molecular Genetics and Metabolism 93 (4): 371–80. Apr 2008. doi:10.1016/j.ymgme.2007.10.135. PMID 18164639.
14. ↑ "Pyruvate dehydrogenase complex deficiency caused by ubiquitination and proteasome-mediated degradation of the E1 subunit". The Journal of Biological Chemistry 283 (1): 237–43. Jan 2008. doi:10.1074/jbc.M704748200. PMID 17923481.

## Further reading

* "Structural basis for flip-flop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase". The Journal of Biological Chemistry 278 (23): 21240–6. Jun 2003. doi:10.1074/jbc.M300339200. PMID 12651851.
* "Mutations of the E1beta subunit gene (PDHB) in four families with pyruvate dehydrogenase deficiency". Molecular Genetics and Metabolism 93 (4): 371–80. Apr 2008. doi:10.1016/j.ymgme.2007.10.135. PMID 18164639.
* "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research 16 (1): 55–65. Jan 2006. doi:10.1101/gr.4039406. PMID 16344560.
* "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Research 11 (3): 422–35. Mar 2001. doi:10.1101/gr.GR1547R. PMID 11230166.
* "Mutations in the gene for the E1beta subunit: a novel cause of pyruvate dehydrogenase deficiency". Human Genetics 115 (2): 123–7. Jul 2004. doi:10.1007/s00439-004-1124-8. PMID 15138885. http://www.springer.com/biomed/human+genetics/journal/439.
* "Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs". American Journal of Physiology. Endocrinology and Metabolism 284 (5): E855–62. May 2003. doi:10.1152/ajpendo.00526.2002. PMID 12676647.
* "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. Oct 1997. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
* "Binding of pyruvate dehydrogenase to the core of the human pyruvate dehydrogenase complex". FEBS Letters 582 (3): 468–72. Feb 2008. doi:10.1016/j.febslet.2007.12.041. PMID 18206651.
* "Identification of the catalytic glutamate in the E1 component of human pyruvate dehydrogenase". FEBS Letters 437 (3): 273–7. Oct 1998. doi:10.1016/S0014-5793(98)01249-6. PMID 9824306.
* "Pyruvate dehydrogenase complex deficiency caused by ubiquitination and proteasome-mediated degradation of the E1 subunit". The Journal of Biological Chemistry 283 (1): 237–43. Jan 2008. doi:10.1074/jbc.M704748200. PMID 17923481.
* "Activation and mitochondrial translocation of protein kinase Cdelta are necessary for insulin stimulation of pyruvate dehydrogenase complex activity in muscle and liver cells". The Journal of Biological Chemistry 276 (48): 45088–97. Nov 2001. doi:10.1074/jbc.M105451200. PMID 11577086.
* "MuRF1-dependent regulation of systemic carbohydrate metabolism as revealed from transgenic mouse studies". Journal of Molecular Biology 379 (4): 666–77. Jun 2008. doi:10.1016/j.jmb.2008.03.049. PMID 18468620.
* "The LIFEdb database in 2006". Nucleic Acids Research 34 (Database issue): D415–8. Jan 2006. doi:10.1093/nar/gkj139. PMID 16381901.
* "Organization of the cores of the mammalian pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and their capacities to bind the E1 and E3 components". The Journal of Biological Chemistry 279 (8): 6921–33. Feb 2004. doi:10.1074/jbc.M308172200. PMID 14638692.
* "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–95. Nov 2000. doi:10.1101/gr.143000. PMID 11076863.
* "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. Sep 1996. doi:10.1101/gr.6.9.791. PMID 8889548.
* "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. Jan 1994. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
* "From ORFeome to biology: a functional genomics pipeline". Genome Research 14 (10B): 2136–44. Oct 2004. doi:10.1101/gr.2576704. PMID 15489336.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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PDB gallery

* 3exi: Crystal structure of the pyruvate dehydrogenase (E1p) component of human pyruvate dehydrogenase complex with the subunit-binding domain (SBD) of E2p, but SBD cannot be modeled into the electron density

* 3exe: Crystal structure of the pyruvate dehydrogenase (E1p) component of human pyruvate dehydrogenase complex

* 3exf: Crystal structure of the pyruvate dehydrogenase (E1p) component of human pyruvate dehydrogenase complex

* 1ni4: HUMAN PYRUVATE DEHYDROGENASE

* 3exg: Crystal structure of the pyruvate dehydrogenase (E1p) component of human pyruvate dehydrogenase complex

* 3exh: Crystal structure of the pyruvate dehydrogenase (E1p) component of human pyruvate dehydrogenase complex

* 2ozl: Human pyruvate dehydrogenase S264E variant

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Aldehyde/oxo oxidoreductases (EC 1.2)

1.2.1: NAD or NADP|

* Aldehyde dehydrogenase
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1.2.2: cytochrome|

* Formate dehydrogenase (cytochrome)

1.2.3: oxygen|

* Aldehyde oxidase

1.2.4: disulfide|

* Oxoglutarate dehydrogenase complex
* Pyruvate dehydrogenase
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* BCKDHA
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1.2.7: iron-sulfur protein|

* Pyruvate synthase

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