Enoyl-CoA hydratase: Difference between revisions

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{{protein
{{protein
|Name=enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A dehydrogenase
|Name=enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A dehydrogenase
|caption=
|caption=Enoyl-CoA hydratase hexamer from a rat with active site in orange and substrate in red.
|image=
|image=enzyme hexamer.png
|width=
|width=
|HGNCid=3247
|HGNCid=3247
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|LocusSupplementaryData=-q28
|LocusSupplementaryData=-q28
}}
}}
'''Enoyl-CoA hydratase''' (ECH) or '''crotonase'''<ref>{{Cite web|url=http://www.sbcs.qmul.ac.uk/iubmb/enzyme/EC4/2/1/17.html|title=EC 4.2.1.17|website=www.sbcs.qmul.ac.uk|access-date=2018-09-05}}</ref> is an [[enzyme]] that hydrates the double bond between the second and third [[carbons]] on 2-trans/cis-enoyl-CoA:<ref name=":0">{{Cite journal|last=Allenbach|first=L|last2=Poirier|first2=Y|date=2000|title=Analysis of the Alternative Pathways for the β-Oxidation of Unsaturated Fatty Acids Using Transgenic Plants Synthesizing Polyhydroxyalkanoates in Peroxisomes|journal=Plant Physiology|volume=124|issue=3|pages=1159–1168|issn=0032-0889|pmc=59215|pmid=11080293}}</ref>


{| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"
[[File:Beta-Oxidation2.svg|460x460px]]
! {{chembox header}}| '''Enoyl-CoA Hydratase: active site and substrate''' <!-- replace if not identical with the article name -->
[[Image:enzyme hexamer.png|350px]]
|-
|Crystal structure of Enoyl-CoA Hydratase from a Rat
|-
| Active Site
| Orange
|-
| Substrate
|Red
|-
|}


'''Enoyl-CoA hydratase''' is an [[enzyme]] that hydrates the double bond between the second and third [[carbons]] on acyl-CoA.  This enzyme, also known as crotonase, is essential to [[metabolizing]] [[fatty acids]] to produce both [[acetyl CoA]] and [[energy]].<ref>Bahnson, Brian J., Vernon E. Anderson, and Gregory A. Petsko. "Structural Mechanism of Enoyl-CoA Hydratase: Three Atoms From a Single Water are Added in Either an E1cb Stepwise or Concerted Fashion." Biochemistry 41 (2002): 2621-2629. SciFinder Scholar. 2 December 2007.</ref>  Note the crystal structure at right of enoyl-coa hydratase from a rat.  The crystal structure shows a hexamer formation (not universal, but human enzyme is also hexameric), which leads to the efficiency of this [[protein]].  This enzyme has been discovered to be highly efficient, and allows our bodies to metabolize fatty acids into energy very quickly. In fact this enzyme is so efficient that the [[reaction rate|rate]] is equivalent to that of diffusion-controlled [[Chemical reaction|reactions]].<ref>TEngel, Christian K., Tiila R. Kiema, J. Kalervo Hiltunen, and Rik K. Wierenga. "The Crystal Structure of Enoyl-CoA Hydratase Complexed with Octanoyl-CoA Reveals the Structural Adaptations Required for Binding of a Long Chain Fatty Acid-CoA Molecule." Journal of Molecular Biology 275 (1998): 847-859. SciFinder Scholar. 2 December 2007.</ref>
[[File:Enoyl-CoA hydratase reaction cis.svg]]


==Biological Significance: Metabolism==
ECH is essential to [[metabolizing]] [[fatty acids]] in [[beta oxidation]] to produce both [[acetyl CoA]] and [[energy]] in the form of [[Adenosine triphosphate|ATP]].<ref name=":0" />
Enoyl-CoA hydratase [[catalyzes]] the second step in the breakdown of fatty acids or the second step of [[β-oxidation]] in fatty acid metabolism shown below.  Fatty acid metabolism is how our bodies turn [[fat]]s or [[lipids]] into energy.  When fats come into our bodies, they are generally in the form of triacyl-glycerols.  These must be broken down in order for the fats to pass into our bodies.  When that happens, three fatty acids are released.


In [[fatty acid metabolism]], fatty acids are changed into fatty acyl-CoA. To do this, the [[carboxylate]] which occupies one end of the fatty acid is changed into a [[thioester]] by substituting coenzyme A for the [[hydroxyl group]]. Next the fatty acyl-CoA is [[oxidized]] and broken down into an acetyl-CoA molecule and another acyl-CoA.  The acetyl CoA is then sent to the [[citric acid cycle]] while the remaining acyl-CoA is broken down further into acetyl-CoAs.  The complete breakdown of a fatty acid not only generates acetyl-CoA molecules, but it also generates energy in the form of [[NADH]].  This NADH goes on to be converted into ATP which can be used in other reactions.<ref>Nelson, David L., and Michael M. Cox. Lehninger Principles of Biochemistry. 4th ed. New York: W. H. Freeman and Company, 2005. 637-643.</ref>
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 [[reaction rate|rate]] for short chain fatty acids is equivalent to that of diffusion-controlled [[Chemical reaction|reactions]].<ref name="Engel_1998">{{cite journal|vauthors=Engel CK, Kiema TR, Hiltunen JK, Wierenga RK|title=The crystal structure of enoyl-CoA hydratase complexed with octanoyl-CoA reveals the structural adaptations required for binding of a long chain fatty acid-CoA molecule|journal=Journal of Molecular Biology|volume=275|issue=5|pages=847–59|date=February 1998|pmid=9480773|doi=10.1006/jmbi.1997.1491 }}</ref>


<!-- Image with unknown copyright status removed: [[Image:fatty_acid_catabolism.gif]] -->
==Metabolism==
{| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"
=== Fatty acid metabolism ===
! {{chembox header}}| '''Active Site Orientation''' <!-- replace if not identical with the article name -->
ECH [[catalyzes]] the second step (hydratation) in the breakdown of fatty acids ([[β-oxidation]]).<ref>{{cite book|title=Lehninger principles of biochemistry|last1=Cox|first1=David L.|last2=Nelson|first2=Michael M.|date=2005|publisher=W.H. Freeman|isbn=978-0-7167-4339-2|edition=4th|location=New York|page=647-43|name-list-format=vanc}}</ref> Fatty acid metabolism is how human bodies turn [[fat]]s into energy. Fats in foods are generally in the form of [[Triglycerol|triglycerols]]. These must be broken down in order for the fats to pass into human bodies. When that happens, three fatty acids are released.
|-
|[[Image:active site orientation.png|350px]]
|-
|}


===Leucine metabolism===
===Leucine metabolism===
Line 52: Line 36:


==Mechanism==
==Mechanism==
Enoyl-CoA hydratase (ECH) is used in β-oxidation to add a hydroxyl group and a [[proton]] to the unsaturated [[β-carbon]] on a fatty-acyl CoA. The enzyme functions by providing two [[glutamate]] [[residue (chemistry)|residue]]s as catalytic [[acid]] and [[Base (chemistry)|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.  
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]] [[residue (chemistry)|residue]]s as catalytic [[acid]] and [[Base (chemistry)|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.
 
[[File:Chimera mechanism.gif|thumb|Concerted reaction.]]
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 the enzyme 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, as seen in figure 1. This configuration requires that the active site for this enzyme is extremely rigid, to hold the water in a very specific configuration with regard to the acyl-CoA. The data for a [[reaction mechanism|mechanism]] for this reaction is not conclusive as to whether this reaction is concerted 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.<ref>Bahnson, Brian J., Vernon E. Anderson, and Gregory A. Petsko. "Structural Mechanism of Enoyl-CoA Hydratase: Three Atoms From a Single Water are Added in Either an E1cb Stepwise or Concerted Fashion." Biochemistry 41 (2002): 2621-2629. SciFinder Scholar. 2 December 2007.</ref>  Both mechanisms are shown below.
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 [[reaction mechanism|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]].<ref name="Bahnson_2002">{{cite journal|vauthors=Bahnson BJ, Anderson VE, Petsko GA|date=February 2002|title=Structural mechanism of enoyl-CoA hydratase: three atoms from a single water are added in either an E1cb stepwise or concerted fashion|journal=Biochemistry|volume=41|issue=8|pages=2621–9|doi=10.1021/bi015844p|pmid=11851409}}</ref>
 
{| class="toccolours" border="1" style="float: center; clear: center; margin: 0 0 1em 1em; border-collapse: collapse;"
! {{chembox header}}| '''Reaction Mechanisms''' <!-- replace if not identical with the article name -->
|-
|Figure 2: Both Mechanisms
|Figure 3: Concerted Mechanism
|-
|<!-- Image with unknown copyright status removed: [[Image:mechanism_for_wiki.gif]] -->
|[[Image:chimera mechanism.gif|350px]]
|-
|}
 
The enzyme is mechanistically similar to [[fumarase]].
 
It is classified as {{EC number|4.2.1.17}}.


ECH is mechanistically similar to [[fumarase]].
{{clear}}
==References==
==References==
{{Reflist}}
{{Reflist|32em}}


==External links==
==External links==
* {{MeshName|Enoyl-CoA+Hydratase}}
*{{MeshName|Enoyl-CoA+Hydratase}}
 
{{Lipid metabolism enzymes}}
{{Lipid metabolism enzymes}}
{{Carbon-oxygen lyases}}
{{Carbon-oxygen lyases}}
{{Enzymes}}
{{Enzymes}}
{{Portal bar|Molecular and Cellular Biology|border=no}}
{{Portal bar|Molecular and Cellular Biology|border=no}}
[[Category:EC 4.2.1]]
[[Category:EC 4.2.1]]

Latest revision as of 17:43, 5 September 2018

enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A dehydrogenase
File:Enzyme hexamer.png
Enoyl-CoA hydratase hexamer from a rat with active site in orange and substrate in red.
Identifiers
SymbolEHHADH
Alt. symbolsECHD
Entrez1962
HUGO3247
OMIM607037
RefSeqNM_001966
UniProtQ08426
Other data
EC number4.2.1.17
LocusChr. 3 q26.3-q28

Enoyl-CoA hydratase (ECH) or crotonase[1] is an enzyme that hydrates the double bond between the second and third carbons on 2-trans/cis-enoyl-CoA:[2]

File:Enoyl-CoA hydratase reaction cis.svg

ECH is essential to metabolizing fatty acids in beta 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]

Metabolism

Fatty acid metabolism

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.

Leucine metabolism

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]

Mechanism

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.

File:Chimera mechanism.gif
Concerted reaction.

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.

References

  1. ↑ "EC 4.2.1.17". www.sbcs.qmul.ac.uk. Retrieved 2018-09-05.
  2. ↑ 2.0 2.1 Allenbach, L; Poirier, Y (2000). "Analysis of the Alternative Pathways for the β-Oxidation of Unsaturated Fatty Acids Using Transgenic Plants Synthesizing Polyhydroxyalkanoates in Peroxisomes". Plant Physiology. 124 (3): 1159–1168. ISSN 0032-0889. PMC 59215. PMID 11080293.
  3. ↑ Engel CK, Kiema TR, Hiltunen JK, Wierenga RK (February 1998). "The crystal structure of enoyl-CoA hydratase complexed with octanoyl-CoA reveals the structural adaptations required for binding of a long chain fatty acid-CoA molecule". Journal of Molecular Biology. 275 (5): 847–59. doi:10.1006/jmbi.1997.1491. PMID 9480773.
  4. ↑ Cox DL, Nelson MM (2005). Lehninger principles of biochemistry (4th ed.). New York: W.H. Freeman. p. 647-43. ISBN 978-0-7167-4339-2.
  5. ↑ 5.0 5.1 Wilson JM, Fitschen PJ, Campbell B, Wilson GJ, Zanchi N, Taylor L, Wilborn C, Kalman DS, Stout JR, Hoffman JR, Ziegenfuss TN, Lopez HL, Kreider RB, Smith-Ryan AE, Antonio J (February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". Journal of the International Society of Sports Nutrition. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC 3568064. PMID 23374455.
  6. ↑ 7.0 7.1 Kohlmeier M (May 2015). "Leucine". Nutrient Metabolism: Structures, Functions, and Genes (2nd ed.). Academic Press. pp. 385–388. ISBN 978-0-12-387784-0. Retrieved 6 June 2016. 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
    Figure 8.57: Metabolism of L-leucine
  7. ↑ Bahnson BJ, Anderson VE, Petsko GA (February 2002). "Structural mechanism of enoyl-CoA hydratase: three atoms from a single water are added in either an E1cb stepwise or concerted fashion". Biochemistry. 41 (8): 2621–9. doi:10.1021/bi015844p. PMID 11851409.

External links

Retrieved from "https://www.wikidoc.org/index.php?title=Enoyl-CoA_hydratase&oldid=1532180"