Gamma-butyrobetaine dioxygenase

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BBOX1
Protein BBOX1 PDB 3MS5.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases BBOX1, BBH, BBOX, G-BBH, gamma-BBH, gamma-butyrobetaine hydroxylase 1
External IDs MGI: 1891372 HomoloGene: 2967 GeneCards: BBOX1
RNA expression pattern
PBB GE BBOX1 205363 at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_003986

NM_130452

RefSeq (protein)

NP_003977

NP_569719.1
NP_569719

Location (UCSC) Chr 11: 27.04 – 27.13 Mb Chr 2: 110.26 – 110.31 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Gamma-butyrobetaine dioxygenase (also known as BBOX, GBBH or γ-butyrobetaine hydroxylase) is an enzyme that in humans is encoded by the BBOX1 gene.[3][4] Gamma-butyrobetaine dioxygenase catalyses the formation of L-carnitine from gamma-butyrobetaine, the last step in the L-carnitine biosynthesis pathway.[5] Carnitine is essential for the transport of activated fatty acids across the mitochondrial membrane during mitochondrial beta oxidation.[4] In humans, gamma-butyrobetaine dioxygenase can be found in kidney (high), liver (moderate), and brain (very low).[3][6] BBOX1 has recently been identified as a potential cancer gene on the basis of a large-scale microarray data analysis.[7]

Reaction[edit]

gamma-butyrobetaine dioxygenase
Identifiers
EC number 1.14.11.1
CAS number 9045-31-2
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

The following reaction is catalyzed by gamma-butyrobetaine dioxygenase:

4-trimethylammoniobutanoate (γ-butyrobetaine) + 2-oxoglutarate + O2 3-hydroxy-4-trimethylammoniobutanoate (L-carnitine) + succinate + CO2

The three substrates of this enzyme are 4-trimethylammoniobutanoate (γ-butyrobetaine), 2-oxoglutarate, and O2,[8] 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.[9][10][11][12] The catalytic activity of gamma-butyrobetaine dioxygenase can be stimulated with different metal ions, especially potassium ions.[13]

Both the apo (PDB id: 3N6W)[14] and the holo (PDB id: 3O2G)[15] 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 promiscus 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.[15][16] Gamma-butyrobetaine dioxygenase also catalyses the oxidation of mildronate[17] 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.[18][19] 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).[20]

Inhibition[edit]

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.[21][22][23] Some studies suggested that mildronate may also be beneficial for the treatment of neurological disorder,[24][25] diabetes,[26] and seizures and alcohol intoxication.[27] 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.[28][29][30][31][32] However, there have been no randomized clinical trials to support the use of mildronate to treat any cardiovascular disease.[33][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).[34] 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.[35] Although initial reports suggested mildronate is a non-competitive and non-hydroxylatable analogue of gamma-butyrobetaine,[36] further studies have identified mildronate is indeed a substrate for gamma-butyrobetaine dioxygenase.[15][18][37]

Similar to other 2OG oxygenases, gamma-butyrobetaine dioxygenase can be inhibited by 2OG mimics and aromatic inhibitors such as pyridine 2,4-dicarboxylate.[38] Other reported gamma-butyrobetaine dioxygenase inhibitors include cyclopropyl-substituted gamma-butyrobetaines[39] and 3-(2,2-dimethylcyclopropyl)propanoic acid, which is a mechanism-based enzyme inhibitor.[40]

Assay[edit]

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[41] and 14C-labelled 2OG.[42] 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.[43][44][45] Other analytical methods including mass spectrometry and NMR have also been applied,[15] 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.[16] 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.[46] The fluoride ions released as a result of gamma-butyrobetaine dioxygenase catalyses can be detected by using chemosensors such as protected fluorescein.[47]

See also[edit]

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ a b Vaz FM, van Gool S, Ofman R, Ijlst L, Wanders RJ (Sep 1998). "Carnitine biosynthesis: identification of the cDNA encoding human gamma-butyrobetaine hydroxylase". Biochemical and Biophysical Research Communications. 250 (2): 506–10. doi:10.1006/bbrc.1998.9343. PMID 9753662. 
  4. ^ a b "Entrez Gene: BBOX1 butyrobetaine (gamma), 2-oxoglutarate dioxygenase (gamma-butyrobetaine hydroxylase) 1". 
  5. ^ Paul HS, Sekas G, Adibi SA (Feb 1992). "Carnitine biosynthesis in hepatic peroxisomes. Demonstration of gamma-butyrobetaine hydroxylase activity". European Journal of Biochemistry / FEBS. 203 (3): 599–605. doi:10.1111/j.1432-1033.1992.tb16589.x. PMID 1735445. 
  6. ^ Lindstedt G, Lindstedt S, Nordin I (Oct 1982). "Gamma-butyrobetaine hydroxylase in human kidney". Scandinavian Journal of Clinical and Laboratory Investigation. 42 (6): 477–85. doi:10.3109/00365518209168117. PMID 7156861. 
  7. ^ Dawany NB, Dampier WN, Tozeren A (Jun 2011). "Large-scale integration of microarray data reveals genes and pathways common to multiple cancer types". International Journal of Cancer. 128 (12): 2881–91. doi:10.1002/ijc.25854. PMID 21165954. 
  8. ^ Lindstedt G, Lindstedt S (Aug 1970). "Cofactor requirements of gamma-butyrobetaine hydroxylase from rat liver". The Journal of Biological Chemistry. 245 (16): 4178–86. PMID 4396068. 
  9. ^ Rebouche CJ (Dec 1991). "Ascorbic acid and carnitine biosynthesis". The American Journal of Clinical Nutrition. 54 (6 Suppl): 1147S–1152S. PMID 1962562. 
  10. ^ Nelson PJ, Pruitt RE, Henderson LL, Jenness R, Henderson LM (Jan 1981). "Effect of ascorbic acid deficiency on the in vivo synthesis of carnitine". Biochimica et Biophysica Acta. 672 (1): 123–7. doi:10.1016/0304-4165(81)90286-5. PMID 6783120. 
  11. ^ Rebouche CJ (Dec 1991). "Ascorbic acid and carnitine biosynthesis". The American Journal of Clinical Nutrition. 54 (6 Suppl): 1147S–1152S. PMID 1962562. 
  12. ^ Furusawa H, Sato Y, Tanaka Y, Inai Y, Amano A, Iwama M, Kondo Y, Handa S, Murata A, Nishikimi M, Goto S, Maruyama N, Takahashi R, Ishigami A (Sep 2008). "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. doi:10.1248/bpb.31.1673. PMID 18758058. 
  13. ^ Wehbie RS, Punekar NS, Lardy HA (Mar 1988). "Rat liver gamma-butyrobetaine hydroxylase catalyzed reaction: influence of potassium, substrates, and substrate analogues on hydroxylation and decarboxylation". Biochemistry. 27 (6): 2222–8. doi:10.1021/bi00406a062. PMID 3378057. 
  14. ^ PDB: 3N6W​;Tars K, Rumnieks J, Zeltins A, Kazaks A, Kotelovica S, Leonciks A, Sharipo J, Viksna A, Kuka J, Liepinsh E, Dambrova M (Aug 2010). "Crystal structure of human gamma-butyrobetaine hydroxylase". Biochemical and Biophysical Research Communications. 398 (4): 634–9. doi:10.1016/j.bbrc.2010.06.121. PMID 20599753. 
  15. ^ a b c d PDB: 3O2G​; Leung IK, Krojer TJ, Kochan GT, Henry L, von Delft F, Claridge TD, Oppermann U, McDonough MA, Schofield CJ (Dec 2010). "Structural and mechanistic studies on γ-butyrobetaine hydroxylase". Chemistry & Biology. 17 (12): 1316–24. doi:10.1016/j.chembiol.2010.09.016. PMID 21168767. 
  16. ^ a b Fujimori DG (Dec 2010). "A novel enzymatic rearrangement". Chemistry & Biology. 17 (12): 1269–70. doi:10.1016/j.chembiol.2010.12.003. PMID 21168760. 
  17. ^ Simkhovich BZ, Shutenko ZV, Meirena DV, Khagi KB, Mezapuķe RJ, Molodchina TN, Kalviņs IJ, Lukevics E (Jan 1988). "3-(2,2,2-Trimethylhydrazinium)propionate (THP)--a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties". Biochemical Pharmacology. 37 (2): 195–202. doi:10.1016/0006-2952(88)90717-4. PMID 3342076. 
  18. ^ a b Henry L, Leung IK, Claridge TD, Schofield CJ (Aug 2012). "γ-Butyrobetaine hydroxylase catalyses a Stevens type rearrangement". Bioorganic & Medicinal Chemistry Letters. 22 (15): 4975–8. doi:10.1016/j.bmcl.2012.06.024. PMID 22765904. 
  19. ^ Stevens TS, Creighton EM, Gordon AB, MacNicol M (1928). "CCCCXXIII.—Degradation of quaternary ammonium salts. Part I". J. Chem. Soc.: 3193–3197. doi:10.1039/JR9280003193. 
  20. ^ Loenarz C, Schofield CJ (Mar 2008). "Expanding chemical biology of 2-oxoglutarate oxygenases". Nature Chemical Biology. 4 (3): 152–6. doi:10.1038/nchembio0308-152. PMID 18277970. 
  21. ^ Sesti C, Simkhovich BZ, Kalvinsh I, Kloner RA (Mar 2006). "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. doi:10.1097/01.fjc.0000211732.76668.d2. PMID 16633095. 
  22. ^ Liepinsh E, Vilskersts R, Loca D, Kirjanova O, Pugovichs O, Kalvinsh I, Dambrova M (Dec 2006). "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. doi:10.1097/01.fjc.0000250077.07702.23. PMID 17204911. 
  23. ^ Hayashi Y, Kirimoto T, Asaka N, Nakano M, Tajima K, Miyake H, Matsuura N (May 2000). "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. doi:10.1016/S0014-2999(00)00098-4. PMID 10812052. 
  24. ^ Sjakste N, Gutcaits A, Kalvinsh I (2005). "Mildronate: an antiischemic drug for neurological indications". CNS Drug Reviews. 11 (2): 151–68. doi:10.1111/j.1527-3458.2005.tb00267.x. PMID 16007237. 
  25. ^ Pupure J, Isajevs S, Skapare E, Rumaks J, Svirskis S, Svirina D, Kalvinsh I, Klusa V (Feb 2010). "Neuroprotective properties of mildronate, a mitochondria-targeted small molecule". Neuroscience Letters. 470 (2): 100–5. doi:10.1016/j.neulet.2009.12.055. PMID 20036318. 
  26. ^ Liepinsh E, Skapare E, Svalbe B, Makrecka M, Cirule H, Dambrova M (May 2011). "Anti-diabetic effects of mildronate alone or in combination with metformin in obese Zucker rats". European Journal of Pharmacology. 658 (2-3): 277–83. doi:10.1016/j.ejphar.2011.02.019. PMID 21371472. 
  27. ^ Zvejniece L, Svalbe B, Makrecka M, Liepinsh E, Kalvinsh I, Dambrova M (Sep 2010). "Mildronate exerts acute anticonvulsant and antihypnotic effects". Behavioural Pharmacology. 21 (5-6): 548–55. doi:10.1097/FBP.0b013e32833d5a59. PMID 20661137. 
  28. ^ Dzerve V, Matisone D, Kukulis I, Romanova J, Putane L, Grabauskiene V, Skarda I, Berzina D, Strautmanis J (2005). "Mildronate improves peripheral circulation in patients with chronic heart failure: results of a clinical trial (the first report)" (PDF). Semin Cardiol. 11 (2): 56–64. ISSN 1648-7966. Archived from the original (PDF) on 2012-03-28. 
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  33. ^ "Tennis pro Maria Sharapova says she takes 'full responsibility' for failed drug test". LA Times. 
  34. ^ PDB: 3MS5
  35. ^ Rose NR, McDonough MA, King ON, Kawamura A, Schofield CJ (Aug 2011). "Inhibition of 2-oxoglutarate dependent oxygenases". Chemical Society Reviews. 40 (8): 4364–97. doi:10.1039/c0cs00203h. PMID 21390379. 
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  38. ^ Ng SF, Hanauske-Abel HM, Englard S (Jan 1991). "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. PMID 1988434. 
  39. ^ Petter RC, Banerjee S, Englard S (1990). "Inhibition of γ-butyrobetaine hydroxylase by cyclopropyl-substituted γ-butyrobetaines". J. Org. Chem. 55 (10): 3088–3097. doi:10.1021/jo00297a025. 
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Further reading[edit]