“OGDH”的意思、由来-开放百科全书

The OGDH gene is located on the 7th chromosome, with the specific location being 7p14-p13. There are 26 exons located within the gene.^[3]

Protein

This gene encodes a subunit that catalyzes the oxidative decarboxylation of alpha-ketoglutarate to Succinyl-CoA at its active site in the fourth step of the metabolic citric acid cycle by acting as a base to facilitate the decarboxylation. The main residues responsible for the catalysis are thought to be His 260, Phe 227, Gln685, His 729, Ser302, and His 298.^[4]

Function

This gene encodes one subunit of the 2-oxoglutarate dehydrogenase complex. This complex catalyzes the overall conversion of 2-oxoglutarate (alpha-ketoglutarate) to succinyl-CoA and CO₂ during the citric acid cycle. The protein is located in the mitochondrial matrix and uses thiamine pyrophosphate as a cofactor.^[3] The overall complex furthers catalysis by keeping the necessary substrates for the reaction close within the enzyme, thus creating a situation in which it is more likely that the substrate will be in the favorable conformation and orientation. This enzyme is also part of a larger multienzyme complex that channels the intermediates in the catalysis between subunits of the complex thus minimizing unwanted side reactions. Not only do the subunits ferry products back and forth, but each of the subunits in the E1o homodimer are connected via a cavity lined with acidic residues, thus increasing the dimer's ability to act as a base. The orientation of the cavity allows for direct transfer of the intermediate to the E2o subunit.^[5]

Mechanism

The protein encoded by EGDH is thought to have a single active site. The enzyme also requires two cofactors in order for it to function properly, Thiamine diphosphate and a divalent magnesium ion. The specific mechanism of the subunit is currently unknown; however, there are several theories as to how it functions, among them is the Hexa Uni Ping Pong theory.^[6] Even though the mechanism isn't fully known the kinetic data have been calculated and are as follows: the Km is 0.14 ± 0.04 mM, and the Vmax is 9 ± 3 μmol/(min*mg).^[7]

Regulation

This subunit, known as E1o, catalyzes a rate-limiting step in the citric acid cycle and lies far from equilibrium; the total change in Gibbs free energy is ΔG = −33 kJ/mol. The significant energy change makes it a crucial point of regulation not only for the citric acid cycle, but also for the entire cellular respiration pathway. As such, E1o is inhibited by both NADH and Succinyl-CoA via non competitive feedback inhibition.^[4]

Clinical significance

A congenital deficiency in 2-oxoglutarate dehydrogenase activity is believed to lead to hypotonia, metabolic acidosis, and hyperlactatemia. It 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.^[3]

Interactive pathway map

References

1. ^{{cite journal | vauthors = Koike K, Urata Y, Goto S | title = Cloning and nucleotide sequence of the cDNA encoding human 2-oxoglutarate dehydrogenase (lipoamide) | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 5 | pages = 1963–7 | date = Mar 1992 | pmid = 1542694 | pmc = 48574 | doi = 10.1073/pnas.89.5.1963 }}
2. ^{{cite journal | vauthors = Szabo P, Cai X, Ali G, Blass JP | title = Localization of the gene (OGDH) coding for the E1k component of the alpha-ketoglutarate dehydrogenase complex to chromosome 7p13-p11.2 | journal = Genomics | volume = 20 | issue = 2 | pages = 324–6 | date = Mar 1994 | pmid = 8020988 | doi = 10.1006/geno.1994.1178 }}
3. ^¹²³{{cite web | title = Entrez Gene: oxoglutarate (alpha-ketoglutarate) dehydrogenase (lipoamide)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4967| accessdate = }}
4. ^¹{{cite journal | vauthors = Frank RA, Price AJ, Northrop FD, Perham RN, Luisi BF | title = Crystal structure of the E1 component of the Escherichia coli 2-oxoglutarate dehydrogenase multienzyme complex | journal = Journal of Molecular Biology | volume = 368 | issue = 3 | pages = 639–51 | date = May 2007 | pmid = 17367808 | doi = 10.1016/j.jmb.2007.01.080 }}
5. ^{{cite book | title = Principles of Biochemistry | chapter = Chapter 18, Mitochondrial ATP synthesis | first1 = Donald J. | last1 = Voet | first2 = Judith G. | last2 = Voet | first3 = Charlotte W. | last3 = Pratt | publisher = Wiley | year = 2010 | isbn = 978-0-470-23396-2 | page = 669 | edition = 4th | name-list-format = vanc }}
6. ^{{cite journal | vauthors = McMinn CL, Ottaway JH | title = Studies on the mechanism and kinetics of the 2-oxoglutarate dehydrogenase system from pig heart | journal = The Biochemical Journal | volume = 161 | issue = 3 | pages = 569–81 | date = Mar 1977 | pmid = 192200 | doi=10.1042/bj1610569 | pmc=1164543}}
7. ^{{cite journal | vauthors = Leung PS, Rossaro L, Davis PA, Park O, Tanaka A, Kikuchi K, Miyakawa H, Norman GL, Lee W, Gershwin ME | title = Antimitochondrial antibodies in acute liver failure: implications for primary biliary cirrhosis | journal = Hepatology | volume = 46 | issue = 5 | pages = 1436–42 | date = Nov 2007 | pmid = 17657817 | doi = 10.1002/hep.21828 | pmc=3731127}}

Structure

Gene