Biology:Gamma-butyrobetaine dioxygenase

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


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Generic protein structure example

Gamma-butyrobetaine dioxygenase (also known as BBOX, GBBH or γ-butyrobetaine hydroxylase) is an enzyme that in humans is encoded by the BBOX1 gene.[1][2] Gamma-butyrobetaine dioxygenase catalyses the formation of L-carnitine from gamma-butyrobetaine, the last step in the L-carnitine biosynthesis pathway.[3] Carnitine is essential for the transport of activated fatty acids across the mitochondrial membrane during mitochondrial beta oxidation.[2] In humans, gamma-butyrobetaine dioxygenase can be found in the kidney (high), liver (moderate), and brain (very low).[1][4] BBOX1 has recently been identified as a potential cancer gene based on a large-scale microarray data analysis.[5]

Reaction

gamma-butyrobetaine dioxygenase
Identifiers
EC number1.14.11.1
CAS number9045-31-2
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

Gamma-butyrobetaine dioxygenase belongs to the 2-oxoglutarate (2OG)-dependent dioxygenase superfamily. It catalyses the following reaction:

4-trimethylammoniobutanoate (γ-butyrobetaine) + 2-oxoglutarate + O2 [math]\displaystyle{ \rightleftharpoons }[/math] 3-hydroxy-4-trimethylammoniobutanoate (L-carnitine) + succinate + CO2

The three substrates of this enzyme are 4-trimethylammoniobutanoate (γ-butyrobetaine), 2-oxoglutarate, and O2,[6] whereas its three products are 3-hydroxy-4-trimethylammoniobutanoate (L-carnitine), succinate, and carbon dioxide.

This enzyme belongs to the family of oxidoreductases, specifically those acting on paired donors, with O2 as oxidant and incorporation or reduction of oxygen. The oxygen incorporated need not be derived from O2 with 2-oxoglutarate as one donor, and incorporation of one atom of oxygen into each donor. This enzyme participates in lysine degradation. Iron is a cofactor for gamma-butyrobetaine dioxygenase. Similar to many other 2OG oxygenases, the activity of gamma-butyrobetaine dioxygenase can be stimulated by reducing agents such as ascorbate and glutathione.[7][8][9][10] The catalytic activity of gamma-butyrobetaine dioxygenase can be stimulated with different metal ions, especially potassium ions.[11]

Both the apo (PDB id: 3N6W)[12] and the holo (PDB id: 3O2G)[13] structures of gamma-butyrobetaine dioxygenase have been solved, demonstrating an induced fit mechanism may contribute to the catalytic activity of gamma-butyrobetaine dioxygenase.

Gamma-butyrobetaine dioxygenase is promiscuous in substrate selectivity and it processes a number of modified substrates, including the natural catalytic products L-carnitine and D-carnitine, forming 3-dehydrocarnitine and trimethylaminoacetone.[13][14] Gamma-butyrobetaine dioxygenase also catalyses the oxidation of mildronate[15] to form multiple products including malonic acid semialdehyde, dimethylamine, formaldehyde and (1-methylimidazolidin-4-yl)acetic acid, which is proposed to be formed via a Stevens rearrangement mechanism.[16][17] Gamma-butyrobetaine dioxygenase is unique among other human 2OG oxygenases that it catalyses both hydroxylation (e.g.: L-carnitine), demethylation (e.g.: formaldehyde) and C-C bond formation (e.g.: (1-methylimidazolidin-4-yl)acetic acid).[18]

Inhibition

Gamma-butyrobetaine dioxygenase is an inhibition target for 3-(2,2,2-trimethylhydraziniumyl)propionate (mildronate, also known as THP, MET-88, Meldonium or Quarterine). Mildronate is offered, clinically, to non-U.S. markets, in treatment of angina and myocardial infarction.[19][20][21] Some studies suggested that mildronate may also be beneficial for the treatment of neurological disorder,[22][23] diabetes,[24] and seizures and alcohol intoxication.[25] Mildronate is currently manufactured and marketed by Grindeks, a pharmaceutical company based in Latvia. To date, at least five clinical trial reports were published in peer-reviewed journals documenting the efficacy and safety of mildronate on the treatments of angina, stroke and chronic heart failure.[26][27][28][29][30] However, there have been no randomized clinical trials to support the use of mildronate to treat any cardiovascular disease.[31][better source needed]

Mildronate has a similar structure to the natural substrate gamma-butyrobetaine, with a NH group replacing the CH2 of gamma-butyrobetaine at the C-4 position. A crystal structure of mldronate in complex with gamma-butyrobetaine dioxygenase was published, and it suggests mildronate bind to gamma-butyrobetaine dioxygenase in exactly the same way as gamma-butyrobetaine (PDB id: 3MS5).[32] To date, most enzyme inhibitors for human 2OG oxygenases bind to the cosubstrate 2OG binding site; mildronate is a rare example of a non-peptidyl substrate mimic inhibitor.[33] Although initial reports suggested mildronate is a non-competitive and non-hydroxylatable analogue of gamma-butyrobetaine,[34] further studies have identified mildronate is indeed a substrate for gamma-butyrobetaine dioxygenase.[13][16][35]

Similar to other 2OG oxygenases, gamma-butyrobetaine dioxygenase can be inhibited by 2OG mimics and aromatic inhibitors such as pyridine 2,4-dicarboxylate.[36] Other reported gamma-butyrobetaine dioxygenase inhibitors include cyclopropyl-substituted gamma-butyrobetaines[37] and 3-(2,2-dimethylcyclopropyl)propanoic acid, which is a mechanism-based enzyme inhibitor.[38]

Assay

Several in vitro biochemical assays have been applied to monitor the catalytic activity of gamma-butyrobetaine dioxygenase. Early methods have mainly focused on the use of radiolabeled compounds, including 14C-labelled gamma-butyrobetaine[39] and 14C-labelled 2OG.[40] Enzyme-coupled method have also been applied to detect carnitine formation, by using the enzyme carnitine acetyltransferase and 14C-labelled acetyl-coenzyme A to give labelled acetylcarnitine for detection. Using this method, it is possible to detect carnitine concentration down to the pico-molar range.[41][42][43] Other analytical methods including mass spectrometry and NMR have also been applied,[13] and they are in particularly useful for the study of the coupling ratio between 2OG oxidation and substrate formation, and for the characterisation of unknown enzymatic products.[14] However, these methods are often not suitable for high-throughput screening and require expensive instrumentation. A potentially high-throughput fluorescence-based assay has also been proposed by using a fluorinated-gamma-butyrobetaine analog.[44] The fluoride ions released as a result of gamma-butyrobetaine dioxygenase catalyses can be detected by using chemosensors such as protected fluorescein.[45]

See also

References

  1. ↑ 1.0 1.1 "Carnitine biosynthesis: identification of the cDNA encoding human gamma-butyrobetaine hydroxylase". Biochemical and Biophysical Research Communications 250 (2): 506–10. Sep 1998. doi:10.1006/bbrc.1998.9343. PMID 9753662. 
  2. ↑ 2.0 2.1 "Entrez Gene: BBOX1 butyrobetaine (gamma), 2-oxoglutarate dioxygenase (gamma-butyrobetaine hydroxylase) 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8424. 
  3. ↑ "Carnitine biosynthesis in hepatic peroxisomes. Demonstration of gamma-butyrobetaine hydroxylase activity". European Journal of Biochemistry 203 (3): 599–605. Feb 1992. doi:10.1111/j.1432-1033.1992.tb16589.x. PMID 1735445. 
  4. ↑ "Gamma-butyrobetaine hydroxylase in human kidney". Scandinavian Journal of Clinical and Laboratory Investigation 42 (6): 477–85. Oct 1982. doi:10.3109/00365518209168117. PMID 7156861. 
  5. ↑ "Large-scale integration of microarray data reveals genes and pathways common to multiple cancer types". International Journal of Cancer 128 (12): 2881–91. Jun 2011. doi:10.1002/ijc.25854. PMID 21165954. 
  6. ↑ "Cofactor requirements of gamma-butyrobetaine hydroxylase from rat liver". The Journal of Biological Chemistry 245 (16): 4178–86. Aug 1970. doi:10.1016/S0021-9258(18)62901-1. PMID 4396068. 
  7. ↑ "Ascorbic acid and carnitine biosynthesis". The American Journal of Clinical Nutrition 54 (6 Suppl): 1147S–1152S. Dec 1991. doi:10.1093/ajcn/54.6.1147s. PMID 1962562. 
  8. ↑ "Effect of ascorbic acid deficiency on the in vivo synthesis of carnitine". Biochimica et Biophysica Acta (BBA) - General Subjects 672 (1): 123–7. Jan 1981. doi:10.1016/0304-4165(81)90286-5. PMID 6783120. 
  9. ↑ "Ascorbic acid and carnitine biosynthesis". The American Journal of Clinical Nutrition 54 (6 Suppl): 1147S–1152S. Dec 1991. doi:10.1093/ajcn/54.6.1147s. PMID 1962562. http://www.ajcn.org/content/54/6/1147S.abstract. 
  10. ↑ "Vitamin C is not essential for carnitine biosynthesis in vivo: verification in vitamin C-depleted senescence marker protein-30/gluconolactonase knockout mice". Biological & Pharmaceutical Bulletin 31 (9): 1673–9. Sep 2008. doi:10.1248/bpb.31.1673. PMID 18758058. 
  11. ↑ "Rat liver gamma-butyrobetaine hydroxylase catalyzed reaction: influence of potassium, substrates, and substrate analogues on hydroxylation and decarboxylation". Biochemistry 27 (6): 2222–8. Mar 1988. doi:10.1021/bi00406a062. PMID 3378057. 
  12. ↑ PDB: 3N6W​;"Crystal structure of human gamma-butyrobetaine hydroxylase". Biochemical and Biophysical Research Communications 398 (4): 634–9. Aug 2010. doi:10.1016/j.bbrc.2010.06.121. PMID 20599753. 
  13. ↑ 13.0 13.1 13.2 13.3 PDB: 3O2G​; "Structural and mechanistic studies on γ-butyrobetaine hydroxylase". Chemistry & Biology 17 (12): 1316–24. Dec 2010. doi:10.1016/j.chembiol.2010.09.016. PMID 21168767. 
  14. ↑ 14.0 14.1 "A novel enzymatic rearrangement". Chemistry & Biology 17 (12): 1269–70. Dec 2010. doi:10.1016/j.chembiol.2010.12.003. PMID 21168760. 
  15. ↑ "3-(2,2,2-Trimethylhydrazinium)propionate (THP)--a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties". Biochemical Pharmacology 37 (2): 195–202. Jan 1988. doi:10.1016/0006-2952(88)90717-4. PMID 3342076. 
  16. ↑ 16.0 16.1 "γ-Butyrobetaine hydroxylase catalyses a Stevens type rearrangement". Bioorganic & Medicinal Chemistry Letters 22 (15): 4975–8. Aug 2012. doi:10.1016/j.bmcl.2012.06.024. PMID 22765904. 
  17. ↑ "CCCCXXIII.—Degradation of quaternary ammonium salts. Part I". J. Chem. Soc.: 3193–3197. 1928. doi:10.1039/JR9280003193. 
  18. ↑ "Expanding chemical biology of 2-oxoglutarate oxygenases". Nature Chemical Biology 4 (3): 152–6. Mar 2008. doi:10.1038/nchembio0308-152. PMID 18277970. 
  19. ↑ "Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics". Journal of Cardiovascular Pharmacology 47 (3): 493–9. Mar 2006. doi:10.1097/01.fjc.0000211732.76668.d2. PMID 16633095. 
  20. ↑ "Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction". Journal of Cardiovascular Pharmacology 48 (6): 314–9. Dec 2006. doi:10.1097/01.fjc.0000250077.07702.23. PMID 17204911. 
  21. ↑ "Beneficial effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction". European Journal of Pharmacology 395 (3): 217–24. May 2000. doi:10.1016/S0014-2999(00)00098-4. PMID 10812052. 
  22. ↑ "Mildronate: an antiischemic drug for neurological indications". CNS Drug Reviews 11 (2): 151–68. 2005. doi:10.1111/j.1527-3458.2005.tb00267.x. PMID 16007237. 
  23. ↑ "Neuroprotective properties of mildronate, a mitochondria-targeted small molecule". Neuroscience Letters 470 (2): 100–5. Feb 2010. doi:10.1016/j.neulet.2009.12.055. PMID 20036318. 
  24. ↑ "Anti-diabetic effects of mildronate alone or in combination with metformin in obese Zucker rats". European Journal of Pharmacology 658 (2–3): 277–83. May 2011. doi:10.1016/j.ejphar.2011.02.019. PMID 21371472. 
  25. ↑ "Mildronate exerts acute anticonvulsant and antihypnotic effects". Behavioural Pharmacology 21 (5–6): 548–55. Sep 2010. doi:10.1097/FBP.0b013e32833d5a59. PMID 20661137. 
  26. ↑ "Mildronate improves peripheral circulation in patients with chronic heart failure: results of a clinical trial (the first report)". Semin Cardiol 11 (2): 56–64. 2005. ISSN 1648-7966. http://www.seminarsincardiology.com/pdf/Seminars-2005-11-2-56-64.pdf. 
  27. ↑ "Mildronate improves carotid baroreceptor reflex function in patients with chronic heart failure". Semin Cardiovasc Med 13: 6. 2008. http://www.seminarsincardiology.com/pdf/SeminarsCVMed-2007-13-6.pdf. 
  28. ↑ "Mildronate improves the exercise tolerance in patients with stable angina: results of a long term clinical trial". Semin Cardiovasc Med 16: 3. 2010. http://www.seminarsincardiology.com/pdf/SeminarsCVMed-2010-16-3.pdf. 
  29. ↑ "A dose-dependent improvement in exercise tolerance in patients with stable angina treated with mildronate: a clinical trial "MILSS I"". Medicina 47 (10): 544–51. 2011. doi:10.3390/medicina47100078. PMID 22186118. 
  30. ↑ "Efficacy and safety of mildronate for acute ischemic stroke: a randomized, double-blind, active-controlled phase II multicenter trial". Clinical Drug Investigation 33 (10): 755–60. Oct 2013. doi:10.1007/s40261-013-0121-x. PMID 23949899. 
  31. ↑ "Tennis pro Maria Sharapova says she takes 'full responsibility' for failed drug test". LA Times. 8 March 2016. http://www.latimes.com/sports/sportsnow/la-sp-sn-maria-sharapova-drug-test-20160307-story.html. 
  32. ↑ PDB: 3MS5​
  33. ↑ "Inhibition of 2-oxoglutarate dependent oxygenases". Chemical Society Reviews 40 (8): 4364–97. Aug 2011. doi:10.1039/c0cs00203h. PMID 21390379. 
  34. ↑ "Purification and characterization of the rat liver gamma-butyrobetaine hydroxylase". Molecular and Cellular Biochemistry 178 (1–2): 163–8. Jan 1998. doi:10.1023/A:1006849713407. PMID 9546596. 
  35. ↑ "Development and characterization of an animal model of carnitine deficiency". European Journal of Biochemistry 268 (6): 1876–87. Mar 2001. doi:10.1046/j.1432-1327.2001.02065.x. PMID 11248709. 
  36. ↑ "Cosubstrate binding site of Pseudomonas sp. AK1 gamma-butyrobetaine hydroxylase. Interactions with structural analogs of alpha-ketoglutarate". The Journal of Biological Chemistry 266 (3): 1526–33. Jan 1991. doi:10.1016/S0021-9258(18)52326-7. PMID 1988434. 
  37. ↑ "Inhibition of γ-butyrobetaine hydroxylase by cyclopropyl-substituted γ-butyrobetaines". J. Org. Chem. 55 (10): 3088–3097. 1990. doi:10.1021/jo00297a025. 
  38. ↑ "Mechanism-based inhibition of bacterial γ-butyrobetaine hydroxylase". J. Am. Chem. Soc. 112 (2): 834–838. 1990. doi:10.1021/ja00158a051. 
  39. ↑ "γ-Butyrobetaine Hydroxylase from Pseudomonas sp AK 1". Biochemistry 9 (22): 4336–4342. 1970. doi:10.1021/bi00824a014. PMID 5472709. 
  40. ↑ "Purification and properties of γ-butyrobetaine hydroxylase from Pseudomonas species AK 1". Biochemistry 16 (10): 2181–2188. 1977. doi:10.1021/bi00629a022. PMID 861203. 
  41. ↑ "A method for the determination of carnitine in the picomole range". Clin. Chim. Acta 37: 235–243. 1972. doi:10.1016/0009-8981(72)90438-X. PMID 5022087. 
  42. ↑ "Carnitine levels in human serum in health and disease". Clin. Chim. Acta 57 (1): 55–61. 1974. doi:10.1016/0009-8981(74)90177-6. PMID 4279150. 
  43. ↑ "Microdetermination of (−)carnitine and carnitine acetyltransferase activity". Anal. Biochem. 79 (1–2): 190–201. 1976. doi:10.1016/0003-2697(77)90393-1. PMID 869176. 
  44. ↑ "Development and application of a fluoride-detection-based fluorescence assay for γ-butyrobetaine hydroxylase". ChemBioChem 13 (11): 1559–63. Jul 2012. doi:10.1002/cbic.201200256. PMID 22730246. 
  45. ↑ "Recognition and sensing of fluoride anion". Chemical Communications (20): 2809–29. May 2009. doi:10.1039/B902069A. PMID 19436879. 

Further reading



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