enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A dehydrogenase | |||||||
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Identifiers | |||||||
Symbol | EHHADH | ||||||
Alt. symbols | ECHD | ||||||
NCBI gene | 1962 | ||||||
HGNC | 3247 | ||||||
OMIM | 607037 | ||||||
RefSeq | NM_001966 | ||||||
UniProt | Q08426 | ||||||
Other data | |||||||
EC number | 4.2.1.17 | ||||||
Locus | Chr. 3 q26.3-q28 | ||||||
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Enoyl-CoA hydratase (ECH) or crotonase[1] is an enzyme EC 4.2.1.17 that hydrates the double bond between the second and third carbons on 2-trans/cis-enoyl-CoA:[2]
ECH is essential to metabolizing fatty acidsinbeta oxidation to produce both acetyl CoA and energy in the form of ATP.[2]
ECH of rats is a hexameric protein (this trait is not universal, but human enzyme is also hexameric), which leads to the efficiency of this enzyme as it has 6 active sites. This enzyme has been discovered to be highly efficient, and allows people to metabolize fatty acids into energy very quickly. In fact this enzyme is so efficient that the rate for short chain fatty acids is equivalent to that of diffusion-controlled reactions.[3]
ECH catalyzes the second step (hydratation) in the breakdown of fatty acids (β-oxidation).[4] Fatty acid metabolism is how human bodies turn fats into energy. Fats in foods are generally in the form of triglycerols. These must be broken down in order for the fats to pass into human bodies. When that happens, three fatty acids are released.
Muscle: α-Ketoisocaproate (α-KIC)
Liver: α-Ketoisocaproate (α-KIC)
Excreted
in urine (10–40%)
β-Hydroxy β-methylglutaryl-CoA
(HMG-CoA)
β-Methylcrotonyl-CoA
(MC-CoA)
β-Methylglutaconyl-CoA
(MG-CoA)
Enoyl-CoA hydratase
Unknown
Human metabolic pathway for HMB and isovaleryl-CoA relative to L-leucine.[5][6][7] Of the two major pathways, L-leucine is mostly metabolized into isovaleryl-CoA, while only about 5% is metabolized into HMB.[5][6][7]
enzyme |
ECH is used in β-oxidation to add a hydroxyl group and a proton to the unsaturated β-carbon on a fatty-acyl CoA. ECH functions by providing two glutamate residues as catalytic acid and base. The two amino acids hold a water molecule in place, allowing it to attack in a syn addition to an α-β unsaturated acyl-CoA at the β-carbon. The α-carbon then grabs another proton, which completes the formation of the beta-hydroxy acyl-CoA.
It is also known from experimental data that no other sources of protons reside in the active site. This means that the proton which the α-carbon grabs is from the water that just attacked the β-carbon. What this implies is that the hydroxyl group and the proton from water are both added from the same side of the double bond, a syn addition. This allows ECH to make an S stereoisomer from 2-trans-enoyl-CoA and an R stereoisomer from the 2-cis-enoyl-CoA. This is made possible by the two glutamate residues which hold the water in position directly adjacent to the α-β unsaturated double bond. This configuration requires that the active site for ECH is extremely rigid, to hold the water in a very specific configuration with regard to the acyl-CoA. The data for a mechanism for this reaction is not conclusive as to whether this reaction is concerted (shown in the picture) or occurs in consecutive steps. If occurring in consecutive steps, the intermediate is identical to that which would be generated from an E1cB-elimination reaction.[8]
ECH is mechanistically similar to fumarase.
HMB is a metabolite of the amino acid leucine (Van Koverin and Nissen 1992), an essential amino acid. The first step in HMB metabolism is the reversible transamination of leucine to [α-KIC] that occurs mainly extrahepatically (Block and Buse 1990). Following this enzymatic reaction, [α-KIC] may follow one of two pathways. In the first, HMB is produced from [α-KIC] by the cytosolic enzyme KIC dioxygenase (Sabourin and Bieber 1983). The cytosolic dioxygenase has been characterized extensively and differs from the mitochondrial form in that the dioxygenase enzyme is a cytosolic enzyme, whereas the dehydrogenase enzyme is found exclusively in the mitochondrion (Sabourin and Bieber 1981, 1983). Importantly, this route of HMB formation is direct and completely dependent of liver KIC dioxygenase. Following this pathway, HMB in the cytosol is first converted to cytosolic β-hydroxy-β-methylglutaryl-CoA (HMG-CoA), which can then be directed for cholesterol synthesis (Rudney 1957) (Fig. 1). In fact, numerous biochemical studies have shown that HMB is a precursor of cholesterol (Zabin and Bloch 1951; Nissen et al. 2000).
Energy fuel: Eventually, most Leu is broken down, providing about 6.0kcal/g. About 60% of ingested Leu is oxidized within a few hours ... Ketogenesis: A significant proportion (40% of an ingested dose) is converted into acetyl-CoA and thereby contributes to the synthesis of ketones, steroids, fatty acids, and other compounds
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4.2.1: Hydro-Lyases |
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4.2.2: Acting on polysaccharides |
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4.2.3: Acting on phosphates |
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4.2.99: Other |
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Activity |
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Regulation |
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Classification |
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