View source for Acyl-CoA

{{Short description|Group of coenzymes that metabolize fatty acids}}
[[File:Acyl-CoA2.svg|thumb|right|General chemical structure of an acyl-CoA, where R is a carboxylic acid side chain]]
'''Acyl-CoA''' is a group of [[coenzyme A|CoA]]-based [[coenzyme]]s that metabolize [[carboxylic acid]]s. [[Fatty acyl-CoA]]'s are susceptible to [[beta oxidation]], forming, ultimately, [[acetyl-CoA]]. The acetyl-CoA enters the [[citric acid cycle]], eventually forming several equivalents of [[Adenosine triphosphate|ATP]].  In this way, fats are converted to ATP, the common biochemical energy carrier.
==Functions==
===Fatty acid activation===
Fats are broken down by conversion to acyl-CoA. This conversion is one response to high energy demands such as exercise.<ref name=":0">{{Citation|last1=Talley|first1=Jacob T.|title=Biochemistry, Fatty Acid Oxidation|date=2020|url=http://www.ncbi.nlm.nih.gov/books/NBK556002/|work=StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=32310462|access-date=2021-02-23|last2=Mohiuddin|first2=Shamim S.}}</ref>
The oxidative degradation of fatty acids is a two-step process, catalyzed by [[Long-chain-fatty-acid—CoA ligase|acyl-CoA synthetase]].<ref>{{Cite journal |last1=Grevengoed |first1=Trisha J. |last2=Klett |first2=Eric L. |last3=Coleman |first3=Rosalind A. |date=2014-07-17 |title=Acyl-CoA Metabolism and Partitioning |journal=Annual Review of Nutrition |language=en |volume=34 |issue=1 |pages=1–30 |doi=10.1146/annurev-nutr-071813-105541 |issn=0199-9885 |pmc=5881898 |pmid=24819326}}</ref> Fatty acids are converted to their acyl phosphate, the precursor to acyl-CoA. The latter conversion is mediated by acyl-CoA synthase"
:acyl-P + HS-CoA →  acyl-S-CoA + P<sub>i</sub>  +  H<sup>+</sup>
Three types of acyl-CoA synthases are employed, depending on the chain length of the fatty acid.<ref>{{cite book |doi=10.1016/B978-0-12-803550-4.00015-X |chapter=Lipid Metabolism |title=Medical Biochemistry |pages=325–365 |year=2017 |last1=Blanco |first1=Antonio |last2=Blanco |first2=Gustavo |isbn=978-0-12-803550-4 }}</ref> For example, the substrates for medium chain acyl-CoA synthase are 4-11 carbon fatty acids.<ref name="Bhagavan et al 2015">{{cite book |doi=10.1016/B978-0-12-416687-5.00016-6 |chapter=Lipids I: Fatty Acids and Eicosanoids |title=Essentials of Medical Biochemistry |pages=269–297 |year=2015 |last1=Bhagavan |first1=N.V. |last2=Ha |first2=Chung-Eun |isbn=978-0-12-416687-5 }}</ref> The enzyme acyl-CoA thioesterase takes of the acyl-CoA to form a free fatty acid and coenzyme A.<ref name="Bhagavan et al 2015" />
=== Beta oxidation of acyl-CoA ===
The second step of fatty acid degradation is beta oxidation. Beta oxidation occurs in mitochondria.<ref name=":1">{{Cite web|title=Fatty acid beta oxidation {{!}} Abcam|url=https://www.abcam.com/pathways/fatty-acid-oxidation|access-date=2021-02-23|website=www.abcam.com}}</ref>  After formation in the cytosol, acyl-CoA is transported into the mitochondria, the location of beta oxidation.  Transport of acyl-CoA into the mitochondria requires [[Carnitine palmitoyltransferase I|carnitine palmitoyltransferase 1]] (CPT1), which converts acyl-CoA into acylcarnitine, which gets transported into the mitochondrial matrix.<ref name=":0" />  Once in the matrix, acylcarnitine is converted back to acyl-CoA by CPT2.<ref name=":1" />  Beta oxidation may begin now that Acyl-CoA is in the mitochondria.  
Beta oxidation of acyl-CoA occurs in four steps.
1.      [[Acyl-CoA dehydrogenase]] catalyzes dehydrogenation of the acyl-CoA, creating a double bond between the alpha and beta carbons.<ref name=":2">{{Cite web|date=2016-02-26|title=6.11: Fatty Acid Oxidation|url=https://bio.libretexts.org/Bookshelves/Biochemistry/Book%3A_Biochemistry_Free_and_Easy_(Ahern_and_Rajagopal)/06%3A_Metabolism_I_-_Oxidative_Reductive_Processes/6.11%3A_Fatty_Acid_Oxidation|access-date=2021-02-23|website=Biology LibreTexts|language=en}}</ref>  [[Flavin adenine dinucleotide|FAD]] is the hydrogen acceptor, yielding FADH2.<ref name=":3">{{Cite web|date=2017-06-03|title=Beta Oxidation|url=https://biologydictionary.net/beta-oxidation/|access-date=2021-02-23|website=Biology Dictionary|language=en-US}}</ref>
2.      [[Enoyl-CoA hydrase]] catalyzes the addition of water across the newly formed double bond to make an alcohol.<ref name=":1" /><ref name=":2" />
3.      [[3-hydroxyacyl-CoA dehydrogenase]] oxidizes the alcohol group to a ketone.<ref name=":1" /> NADH is produced from [[Nicotinamide adenine dinucleotide|NAD+]].<ref name=":2" />
4.      [[HADHB|Thiolase]] cleaves between the [[alpha carbon]] and ketone to release one molecule of [[Acetyl-CoA]] and the Acyl-CoA which is now 2 carbons shorter.<ref name=":2" />
This four step process repeats until acyl-CoA has removed all carbons from the chain, leaving only Acetyl-CoA. During one cycle of beta oxidation, Acyl-CoA creates one molecule of Acetyl-CoA, FADH2, and NADH.<ref name=":3" />  Acetyl-CoA is then used in the [[citric acid cycle]] while FADH2 and NADH are sent to the [[electron transport chain]].<ref name=":4">{{Cite web|title=6.32 Fatty Acid Oxidation (Beta-oxidation) {{!}} Nutrition Flexbook|url=https://courses.lumenlearning.com/suny-nutrition/chapter/6-32-fatty-acid-oxidation-beta-oxidation/|access-date=2021-02-23|website=courses.lumenlearning.com}}</ref> These intermediates all end up providing energy for the body as they are ultimately converted to [[Adenosine triphosphate|ATP]].<ref name=":4" />
[[File:Beta Oxidation Process.png|alt=The process of Beta Oxidation of an activated Acyl-CoA molecule.|thumb|Example of Beta Oxidation using Stearic Acid]]
Beta oxidation, as well as alpha-oxidation, also occurs in the [[peroxisome]].<ref name=":0" /> The peroxisome handles beta oxidation of fatty acids that have more than 20 carbons in their chain because the peroxisome contains [[Very long-chain acyl-CoA synthetase|very-long-chain Acyl-CoA synthetases]].<ref name=":5">{{Cite journal|last1=Reddy|first1=Janardan K|last2=Hashimoto|first2=Takashi|date=2001-07-01|title=PEROXISOMAL β-OXIDATION AND PEROXISOME PROLIFERATOR–ACTIVATED RECEPTOR α: An Adaptive Metabolic System|url=https://www.annualreviews.org/doi/10.1146/annurev.nutr.21.1.193|journal=Annual Review of Nutrition|volume=21|issue=1|pages=193–230|doi=10.1146/annurev.nutr.21.1.193|pmid=11375435|issn=0199-9885}}</ref>  These enzymes are better equipped to oxidize Acyl-CoA with long chains that the mitochondria cannot handle.
==== Example using stearic acid ====
Beta oxidation removes 2 carbons at a time, so in the oxidation of an 18 carbon fatty acid such as [[Stearic acid|Stearic Acid]] 8 cycles will need to occur to completely break down Acyl-CoA.<ref name=":5" /> This will produce 9 Acetyl-CoA that have 2 carbons each, 8 FADH2, and 8 NADH.
==Clinical significance==
Heart muscle primarily metabolizes fat for energy and Acyl-CoA metabolism has been identified<ref>{{cite journal |last1=Goldenberg |first1=Joseph R. |last2=Carley |first2=Andrew N. |last3=Ji |first3=Ruiping |last4=Zhang |first4=Xiaokan |last5=Fasano |first5=Matt |last6=Schulze |first6=P. Christian |last7=Lewandowski |first7=E. Douglas |title=Preservation of Acyl-CoA Attenuates Pathological and Metabolic Cardiac Remodeling Through Selective Lipid Trafficking |journal=Circulation |volume=139 |issue=24 |pages=2765–2777 |date=26 March 2019 |doi=10.1161/CIRCULATIONAHA.119.039610 |pmid=30909726 |pmc=6557671}}
*{{lay source |template=cite news |author=Marti Leitch |title=Scientists find metabolic target to prevent, treat heart failure at earliest stage |url=https://news.osu.edu/scientists-find-metabolic-target-to-prevent-treat-heart-failure-at-earliest-stage |date=March 26, 2019 |work=Ohio State News}}</ref> as a critical molecule in early stage heart muscle pump failure.
Cellular acyl-CoA content correlates with insulin resistance, suggesting that it can mediate lipotoxicity in non-adipose tissues.<ref>{{cite journal |last1=Li |first1=Lei O. |last2=Klett |first2=Eric L. |last3=Coleman |first3=Rosalind A. |title=Acyl-CoA synthesis, lipid metabolism and lipotoxicity |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |date=March 2010 |volume=1801 |issue=3 |pages=246–251 |doi=10.1016/j.bbalip.2009.09.024 |pmid=19818872 |pmc=2824076 }}</ref> Acyl-CoA: diacylglycerol acyltransferase (DGAT) plays an important role in energy metabolism on account of  key enzyme in triglyceride biosynthesis. The synthetic role of DGAT in adipose tissue such as the liver and the intestine, sites where endogenous levels of its activity and triglyceride synthesis are high and comparatively clear. Also, any changes in the activity levels might cause changes in systemic insulin sensitivity and energy homeostasis.<ref>{{cite journal |last1=Yu |first1=Yi-Hao |last2=Ginsberg |first2=Henry |title=The role of acyl-CoA:diacylglycerol acyltransferase (DGAT) in energy metabolism |journal=Annals of Medicine |date=8 July 2009 |volume=36 |issue=4 |pages=252–261 |doi=10.1080/07853890410028429 |pmid=15224651 |s2cid=9174481 |doi-access=free }}</ref>
A rare disease called multiple acyl-CoA dehydrogenase deficiency (MADD)<ref name="Rashmi et al 2017">{{cite journal |last1=Rashmi |first1=S. |last2=Gayathri |first2=N. |last3=Kumar |first3=M. Veerendra |last4=Sumanth |first4=S. |last5=Subasree |first5=R. |last6=Pooja |first6=M. |title=Multiple Acyl CoA dehydrogenase deficiency: Uncommon yet treatable disorder |journal=Neurology India |date=1 January 2017 |volume=65 |issue=1 |pages=177–8 |doi=10.4103/0028-3886.198186 |pmid=28084266 |doi-access=free | url=https://neurologyindia.com/article.asp?issn=0028-3886;year=2017;volume=65;issue=1;spage=177;epage=178;aulast=Pooja}}</ref> is a fatty acid metabolism disorder. Acyl-CoA is important because this enzyme helps make Acyl-CoA from free fatty acids, and this activates the fatty acid to be metabolized. This compromised fatty acid oxidation leads to many different symptoms, including severe symptoms such as cardiomyopathy and liver disease and mild symptoms such as episodic metabolic decomposition, muscle weakness and respiratory failure. MADD is a genetic disorder, caused by a mutation in the ETFA, ETFB, and ETFDH genes. MADD is known as an "autosomal recessive disorder"<ref name="Rashmi et al 2017"/> because for one to get this disorder, one must receive this recessive gene from both parents.
==See also==
* [[Acetyl-CoA]]
* [[Beta oxidation]]
* [[Coenzyme A]]
* [[Acyl CoA dehydrogenase]]
* [[Fatty acid metabolism]]
* [[Fatty acyl-CoA esters]]
==References==
{{Reflist}}
==External links==
* {{MeshName|Acyl+Coenzyme+A}}
{{Fatty-acid metabolism intermediates}}
[[Category:Metabolism]]
[[Category:Thioesters of coenzyme A]]