Crotonase family explained

The crotonase family comprises mechanistically diverse proteins that share a conserved trimeric quaternary structure (sometimes a hexamer consisting of a dimer of trimers), the core of which consists of 4 turns of a (beta/beta/alpha)n superhelix.

Some enzymes in the superfamily have been shown to display dehalogenase, hydratase, and isomerase activities, while others have been implicated in carbon-carbon bond formation and cleavage as well as the hydrolysis of thioesters.^[1] However, these different enzymes share the need to stabilize an enolate anion intermediate derived from an acyl-CoA substrate. This is accomplished by two structurally conserved peptidic NH groups that provide hydrogen bonds to the carbonyl moieties of the acyl-CoA substrates and form an "oxyanion hole". The CoA thioester derivatives bind in a characteristic hooked shape and a conserved tunnel binds the pantetheine group of CoA, which links the 3'-phosphate ADP binding site to the site of reaction.^[2] Enzymes in the crotonase superfamily include:

• Enoyl-CoA hydratase (crotonase;), which catalyses the hydratation of 2-trans-enoyl-CoA into 3-hydroxyacyl-CoA.^[3]
• 3-2trans-enoyl-CoA isomerase (or dodecenoyl-CoA isomerise;), which shifts the 3-double bond of the intermediates of unsaturated fatty acid oxidation to the 2-trans position.^[4]
• 3-hydroxybutyryl-CoA dehydrogenase (crotonase;), a bacterial enzyme involved in the butyrate/butanol-producing pathway.
• 4-Chlorobenzoyl-CoA dehalogenase, a Pseudomonas enzyme which catalyses the conversion of 4-chlorobenzoate-CoA to 4-hydroxybenzoate-CoA.^[5]
• Dienoyl-CoA isomerase, which catalyses the isomerisation of 3-trans,5-cis-dienoyl-CoA to 2-trans,4-trans-dienoyl-CoA.^[6]
• Naphthoate synthase (MenB, or DHNA synthetase;), a bacterial enzyme involved in the biosynthesis of menaquinone (vitamin K2).^[7]
• Carnitine racemase (gene caiD), which catalyses the reversible conversion of crotonobetaine to L-carnitine in Escherichia coli.^[8]
• Methylmalonyl CoA decarboxylase (MMCD;), which has a hexameric structure (dimer of trimers).^[9]
• Carboxymethylproline synthase (CarB), which is involved in carbapenem biosynthesis.^[10]
• 6-oxo camphor hydrolase, which catalyses the desymmetrization of bicyclic beta-diketones to optically active keto acids.^[11]
• The alpha subunit of fatty acid oxidation complex, a multi-enzyme complex that catalyses the last three reactions in the fatty acid beta-oxidation cycle.^[12]
• AUH protein, a bifunctional RNA-binding homologue of enoyl-CoA hydratase.^[13]

Human proteins containing this domain

AUH

CDY2B; CDYL; CDYL2; DCI; ECH1; ECHDC1; ECHDC2; ECHDC3

ECHS1; EHHADH; HADHA; HCA64; HIBCH; PECI;

Notes and References

1. Gerlt JA, Benning MM, Holden HM, Haller T . The crotonase superfamily: divergently related enzymes that catalyze different reactions involving acyl coenzyme a thioesters . Acc. Chem. Res. . 34 . 2 . 145–57. 2001 . 11263873 . 10.1021/ar000053l.
2. Brzozowski AM, Leonard PM, Bennett JP, Whittingham JL, Grogan G . Structural characterization of a beta-diketone hydrolase from the cyanobacterium Anabaena sp. PCC 7120 in native and product-bound forms, a coenzyme A-independent member of the crotonase suprafamily . Biochemistry . 46 . 1 . 137–44. 2007 . 17198383 . 10.1021/bi061900g.
3. Wu J, Kisker C, Whitty A, Feng Y, Rudolph MJ, Bell AF, Hofstein HA, Parikh S, Tonge PJ . Stereoselectivity of enoyl-CoA hydratase results from preferential activation of one of two bound substrate conformers . Chem. Biol. . 9 . 11 . 1247–55. 2002 . 12445775 . 10.1016/S1074-5521(02)00263-6. free .
4. Stoffel W, Muller-Newen G . Mitochondrial 3-2trans-Enoyl-CoA isomerase. Purification, cloning, expression, and mitochondrial import of the key enzyme of unsaturated fatty acid beta-oxidation . Biol. Chem. Hoppe-Seyler . 372 . 8 . 613–624 . 1991 . 1958319 . 10.1515/bchm3.1991.372.2.613.
5. Dunaway-Mariano D, Benning MM, Wesenberg G, Holden HM, Taylor KL, Yang G, ((Liu R-Q)), Xiang H . Structure of 4-chlorobenzoyl coenzyme A dehalogenase determined to 1.8 A resolution: an enzyme catalyst generated via adaptive mutation . Biochemistry . 35 . 25 . 8103–9. 1996 . 8679561 . 10.1021/bi960768p.
6. Hiltunen JK, Wierenga RK, Modis Y, Filppula SA, Novikov DK, Norledge B . The crystal structure of dienoyl-CoA isomerase at 1.5 A resolution reveals the importance of aspartate and glutamate sidechains for catalysis . Structure . 6 . 8 . 957–70. 1998 . 9739087 . 10.1016/s0969-2126(98)00098-7. free .
7. Baker EN, Johnston JM, Arcus VL . Structure of naphthoate synthase (MenB) from Mycobacterium tuberculosis in both native and product-bound forms . Acta Crystallogr. D . 61 . Pt 9. 1199–206. 2005 . 16131752 . 10.1107/S0907444905017531. 2292/9814 . free .
8. Kleber HP, Elssner T, Engemann C, Baumgart K . Involvement of coenzyme A esters and two new enzymes, an enoyl-CoA hydratase and a CoA-transferase, in the hydration of crotonobetaine to L-carnitine by Escherichia coli . Biochemistry . 40 . 37 . 11140–8. 2001 . 11551212 . 10.1021/bi0108812.
9. Gerlt JA, Benning MM, Holden HM, Haller T . New reactions in the crotonase superfamily: structure of methylmalonyl CoA decarboxylase from Escherichia coli . Biochemistry . 39 . 16 . 4630–9. 2000 . 10769118 . 10.1021/bi9928896.
10. Schofield CJ, McDonough MA, Sleeman MC, Sorensen JL, Batchelar ET . Structural and mechanistic studies on carboxymethylproline synthase (CarB), a unique member of the crotonase superfamily catalyzing the first step in carbapenem biosynthesis . J. Biol. Chem. . 280 . 41 . 34956–65 . 2005 . 16096274 . 10.1074/jbc.M507196200 . free .
11. Leonard PM, Grogan G . Structure of 6-oxo camphor hydrolase H122A mutant bound to its natural product, (2S,4S)-alpha-campholinic acid: mutant structure suggests an atypical mode of transition state binding for a crotonase homolog . J. Biol. Chem. . 279 . 30 . 31312–17 . 2004 . 15138275 . 10.1074/jbc.M403514200. free .
12. Resibois-Gregoire A, Dourov N . Electron microscopic study of a case of cerebral glycogenosis . Acta Neuropathol. . 6 . 1 . 70–9. 1966 . 5229654 . 10.1007/BF00691083. 21331079 .
13. Nureki O, Fukai S, Yokoyama S, Muto Y, Kurimoto K . Crystal structure of human AUH protein, a single-stranded RNA binding homolog of enoyl-CoA hydratase . Structure . 9 . 12 . 1253–63. 2001 . 11738050 . 10.1016/S0969-2126(01)00686-4. free .