| enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A dehydrogenase | |||||||
|---|---|---|---|---|---|---|---|
 Enoyl-CoA hydratase hexamer from a rat with active site in orange and substrate in red. | |||||||
| 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. 3q26.3-q28 | ||||||
| |||||||
Enoyl-CoA hydratase (ECH) orcrotonase[1] is anenzymeEC4.2.1.17 that hydrates the double bond between the second and thirdcarbons on 2-trans/cis-enoyl-CoA:[2]
ECH is essential tometabolizingfatty acids inbeta oxidation to produce bothacetyl CoA andenergy in the form ofATP.[2]
ECH of rats is ahexameric 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 therate for short chain fatty acids is equivalent to that of diffusion-controlledreactions.[3]
ECHcatalyzes the second step (hydratation) in the breakdown of fatty acids (β-oxidation).[4] Fatty acid metabolism is how human bodies turnfats into energy. Fats in foods are generally in the form oftriglycerols. 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 enzyme  |
ECH is used in β-oxidation to add a hydroxyl group and aproton to the unsaturatedβ-carbon on a fatty-acyl CoA. ECH functions by providing twoglutamateresidues as catalyticacid andbase. The twoamino acids hold awater molecule in place, allowing it to attack in asyn 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 theactive 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 thedouble bond, a syn addition. This allows ECH to make an Sstereoisomer from 2-trans-enoyl-CoA and an R stereoisomer from the 2-cis-enoyl-CoA. This is made possible by the twoglutamate 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 amechanism 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 anE1cB-elimination reaction.[8]
ECH is mechanistically similar tofumarase.
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
