View source for Template:Leucine metabolism in humans

{{Annotated image 4
| image = HMB biosynthesis and metabolism diagram - no labels.svg
| align = {{{align|right}}}
| width = 600
| height = 436
| image-width = 600
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| header = {{{header|{{when pagename is|Beta-Hydroxy beta-methylbutyric acid=Biosynthesis and metabolism of β-hydroxy β-methylbutyrate in humans|Leucine=Leucine metabolism in humans|other=[[Chemistry:Leucine#Metabolism in humans|Leucine metabolism in humans]]}}}}}
| header_background = {{{header background|#F0F8FF}}}
| caption = {{{caption|Human [[Biology:Metabolic pathway|metabolic pathway]] for {{no selflink|Beta-Hydroxy beta-methylbutyric acid|HMB}} and {{No selflink|isovaleryl-CoA}} relative to {{No selflink|leucine|{{nowrap|{{smallcaps all|L}}-leucine}}}}.{{when pagename is|Beta-Hydroxy beta-methylbutyric acid=<ref name="ISSN position stand 2013" /><ref name="HMB athletic performance-related effects 2011 review" /><ref name="Leucine metabolism" />|other=<ref name="ISSN position stand 2013">{{cite journal | vauthors = 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 | title = International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB) | journal = Journal of the International Society of Sports Nutrition | volume = 10 | issue = 1 | pages = 6 | date = February 2013 | pmid = 23374455 | pmc = 3568064 | doi = 10.1186/1550-2783-10-6}}</ref><ref name="HMB athletic performance-related effects 2011 review">{{cite journal | vauthors = Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH | title = HMB supplementation: clinical and athletic performance-related effects and mechanisms of action | journal = Amino Acids | volume = 40 | issue = 4 | pages = 1015–1025 | date = April 2011 | pmid = 20607321 | doi = 10.1007/s00726-010-0678-0 | quote = 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).<!--<br /><br /> In the second pathway, after transamination, [α-KIC] in liver generates isovaleryl-CoA through the enzymatic action of branched-chain ketoacid dehydrogenase (BCKD) and after several steps, there is production of HMG-CoA through the enzyme HMG-CoA synthase (Fig. 1). Under normal conditions the majority of KIC is converted into isovaleryl-CoA, in which approximately 5% of leucine is metabolized into HMB (Wilson et al. 2008; Van Koverin and Nissen 1992). However, Nissen and Abumrad (1997) provided evidence that the primary fate of HMB is probably conversion to HMG-CoA in the liver, for cholesterol biosynthesis.--> }}</ref>{{when pagename is|Leucine=<ref name="Leucine metabolism" />|other=<ref name="Leucine metabolism">{{cite book | vauthors=Kohlmeier M | title=Nutrient Metabolism: Structures, Functions, and Genes | date=May 2015 | publisher=Academic Press | isbn=978-0-12-387784-0 | pages=385–388 | edition=2nd | section-url=https://books.google.com/books?id=aTQTAAAAQBAJ&pg=PA387&q=beta-hydroxy%20beta-methylbutyrate%20HMB#v=onepage | url=https://books.google.com/books?id=aTQTAAAAQBAJ&printsec=frontcover#v=onepage | accessdate=6 June 2016 | section=Leucine | quote= Energy fuel: Eventually, most Leu is broken down, providing about 6.0kcal/g. About 60% of ingested Leu is oxidized within a few hours&nbsp;... 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}}<br />[https://books.google.com/books?id=aTQTAAAAQBAJ&pg=PA386#v=onepage&q&f=false Figure 8.57: Metabolism of {{smallcaps all|L}}-leucine]</ref>}}}} Of the two major pathways, {{nowrap|{{smallcaps all|L}}-leucine}} is mostly metabolized into isovaleryl-CoA, while only about&nbsp;5% is metabolized into HMB.<ref name="ISSN position stand 2013" /><ref name="HMB athletic performance-related effects 2011 review" /><ref name="Leucine metabolism" />}}}
| alt = Diagram of leucine, HMB, and isovaleryl-CoA metabolism in humans
| annot-font-size = 12
| annotations =
{{Annotation|180|2|{{when pagename is|Leucine={{highlight|'''{{smallcaps all|L}}-Leucine'''}}|other=[[Chemistry:Leucine|{{nowrap|{{smallcaps all|L}}-Leucine}}]]}}|font-size=18}}
{{Annotation|96|37|[[Biology:Branched-chain amino acid aminotransferase|Branched-chain amino<br />acid aminotransferase]]}}
{{Annotation|240|30|[[α-Ketoglutarate]]}}
{{Annotation|243|61|[[Glutamate]]}}
{{Annotation|466|75|[[Glutamate]]}}
{{Annotation|383|30|[[Chemistry:Alanine|Alanine]]}}
{{Annotation|383|62|[[Biology:Pyruvate|Pyruvate]]}}
{{Annotation|75|85|[[Biology:Skeletal muscle|Muscle]]: {{No selflink|Alpha-Ketoisocaproic acid|α-Ketoisocaproate}} (α-KIC)|font-size=15}}
{{Annotation|82|128|[[Biology:Liver|Liver]]: {{No selflink|Alpha-Ketoisocaproic acid|α-Ketoisocaproate}} (α-KIC)|font-size=15}}
{{Annotation|300|106|{{no selflink|Branched-chain α-ketoacid dehydrogenase|Branched-chain α-ketoacid<br />dehydrogenase}} ([[Biology:Mitochondria|mitochondria]])}}
{{Annotation|93|156|[[Biology:4-Hydroxyphenylpyruvate dioxygenase|KIC-dioxygenase]]<br />([[Biology:Cytosol|cytosol]])}}
{{Annotation|465|126|{{when pagename is|Isovaleryl-CoA={{highlight|'''Isovaleryl-CoA'''}}|other=[[Chemistry:Isovaleryl-CoA|Isovaleryl-CoA]]}}|font-size=15}}
{{Annotation|85|198|{{no selflink|Beta-Hydroxy beta-methylbutyric acid|'''β-Hydroxy<br />β-methylbutyrate'''}}<br />('''HMB''')|background-color={{if pagename|Beta-Hydroxy beta-methylbutyric acid=hsla(60,100%,50%,.35)|other=}}|font-size=15}}
{{Annotation|2|205|[[Biology:Excretion|Excreted]]<br />in urine<br />(10–40%)}}


{{Annotation|239|217|{{when pagename is|Beta-Hydroxy beta-methylbutyryl-CoA={{highlight|'''HMB-CoA'''}}|other=[[Chemistry:Beta-Hydroxy beta-methylbutyryl-CoA|HMB-CoA]]}}|font-size=13}}
{{Annotation|175|269|{{when pagename is|HMG-CoA=β-Hydroxy β-methylglutaryl-CoA<br />({{highlight|'''HMG-CoA'''}})|other=[[Chemistry:HMG-CoA|β-Hydroxy β-methylglutaryl-CoA]]<br />(HMG-CoA)}}|font-size=13}}
{{Annotation|445|208|{{when pagename is|Methylcrotonyl-CoA=β-Methylcrotonyl-CoA<br />({{highlight|'''MC-CoA'''}})|other=[[Chemistry:Methylcrotonyl-CoA|β-Methylcrotonyl-CoA]]<br />(MC-CoA)}}|font-size=13}}
{{Annotation|442|269|{{when pagename is|3-Methylglutaconyl-CoA=β-Methylglutaconyl-CoA<br />({{highlight|'''MG-CoA'''}})|other=[[Chemistry:3-Methylglutaconyl-CoA|β-Methylglutaconyl-CoA]]<br />(MG-CoA)}}|font-size=13}}

{{Annotation|395|148|[[Chemistry:Carbon dioxide|CO<sub>2</sub>]]}}
{{Annotation|221|246|[[Chemistry:Carbon dioxide|CO<sub>2</sub>]]}}
{{Annotation|214|163|[[Chemistry:Oxygen|O<sub>2</sub>]]}}
{{Annotation|211|186|[[Chemistry:Carbon dioxide|CO<sub>2</sub>]]}}
{{Annotation|426|239|[[Chemistry:Properties of water|H<sub>2</sub>O]]}}
{{Annotation|458|246|[[Chemistry:Carbon dioxide|CO<sub>2</sub>]]}}
{{Annotation|422|297|[[Chemistry:Properties of water|H<sub>2</sub>O]]}}

{{Annotation|242|316|([[Biology:Liver|liver]])<br />[[HMG-CoA lyase|HMG-CoA<br />lyase]]}}
{{Annotation|314|208|{{when pagename is|Enoyl-CoA hydratase={{highlight|'''Enoyl-CoA hydratase'''}}|other=[[Biology:Enoyl-CoA hydratase|Enoyl-CoA hydratase]]}}}}
{{Annotation|511|163|{{when pagename is|Isovaleryl-CoA dehydrogenase={{highlight|'''Isovaleryl-CoA<br />dehydrogenase'''}}|other=[[Biology:Isovaleryl-CoA dehydrogenase|Isovaleryl-CoA<br />dehydrogenase]]}}|text-align=left|font-size=12}}
{{Annotation|511|238|{{when pagename is|Methylcrotonyl-CoA carboxylase={{highlight|'''MC-CoA<br />carboxylase'''}}|other=[[Biology:Methylcrotonyl-CoA carboxylase|MC-CoA<br />carboxylase]]}}|text-align=left|font-size=12}}
{{Annotation|376|254|{{when pagename is|Methylglutaconyl-CoA hydratase={{highlight|'''MG-CoA<br />hydratase'''}}|other=[[Biology:Methylglutaconyl-CoA hydratase|MG-CoA<br />hydratase]]}}|text-align=center|font-size=12}}
{{Annotation|59|316|[[Biology:HMG-CoA reductase|HMG-CoA<br />reductase]]}}
{{Annotation|410|331|[[HMG-CoA synthase|HMG-CoA&nbsp;<br />synthase]]|text-align=right|font-size=12}}
{{Annotation|205|387|[[Biology:3-Hydroxybutyrate dehydrogenase|β-Hydroxybutyrate<br />dehydrogenase]]|font-size=12|text-align=left}}
{{Annotation|80|385|[[:File:Mevalonate pathway.svg|Mevalonate<br />pathway]]|font-size=12|text-align=left}}
{{Annotation|389|385|[[Biology:Thiolase|Thiolase]]|font-size=12}}
{{Annotation|274|236|Unknown<br />enzyme|font-size=12|text-align=left}}

{{Annotation|152|420|[[Chemistry:Beta-Hydroxybutyric acid|β-Hydroxybutyrate]]|background-color={{when pagename is|Beta-Hydroxybutyric acid=hsla(60,100%,50%,.35)|other=}}|font-size=13}}
{{Annotation|432|395|[[Chemistry:Acetoacetyl-CoA|Acetoacetyl-CoA]]|font-size=13}}
{{Annotation|328|395|[[Chemistry:Acetyl-CoA|Acetyl-CoA]]|font-size=13}}
{{Annotation|164|365|[[Acetoacetate]]|font-size=13}}
{{Annotation|44|365|[[Mevalonate]]|font-size=13}}
{{Annotation|43|420|[[Chemistry:Cholesterol|Cholesterol]]|font-size=13}}

<!--The following annotation is added to the diagram only when the "note" parameter is used to specify its inclusion; it adds an annotated note about the unknown thioesterase enzyme that catalyzes the HMB↔HMB-CoA reaction; this note appears in a reference tooltip.-->
{{#ifeq:{{Yesno-no|{{{note|<noinclude>yes</noinclude>}}}}}|yes|{{Annotation|206|209|{{#tag:ref|This reaction is catalyzed by an unknown [[Biology:Thioesterase|thioesterase]] enzyme.{{#ifeq:{{Yesno-no|{{{note refs named|}}}}}|yes|<ref name="HMB-CoA ⇔ HMB" /><ref name="pmid21918059" />|<ref name="HMB-CoA ⇔ HMB">{{cite web|title=KEGG Reaction: R10759|url=http://www.genome.jp/dbget-bin/www_bget?rn:R10759|website=Kyoto Encyclopedia of Genes and Genomes|publisher=Kanehisa Laboratories|accessdate=24 June 2016}}</ref><ref name="pmid21918059">{{cite journal | vauthors = Mock DM, Stratton SL, Horvath TD, Bogusiewicz A, Matthews NI, Henrich CL, Dawson AM, Spencer HJ, Owen SN, Boysen G, Moran JH | title = Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans | journal = The Journal of Nutrition | volume = 141 | issue = 11 | pages = 1925–1930 | date = November 2011 | pmid = 21918059 | pmc = 3192457 | doi = 10.3945/jn.111.146126 | department = primary source | quote = Metabolic impairment diverts methylcrotonyl CoA to 3-hydroxyisovaleryl CoA in a reaction catalyzed by enoyl-CoA hydratase (22, 23). 3-Hydroxyisovaleryl CoA accumulation can inhibit cellular respiration either directly or via effects on the ratios of acyl CoA:free CoA if further metabolism and detoxification of 3-hydroxyisovaleryl CoA does not occur (22). The transfer to carnitine by 4 carnitine acyl-CoA transferases distributed in subcellular compartments likely serves as an important reservoir for acyl moieties (39–41). 3-Hydroxyisovaleryl CoA is likely detoxified by carnitine acetyltransferase producing 3HIA-carnitine, which is transported across the inner mitochondrial membrane (and hence effectively out of the mitochondria) via carnitine-acylcarnitine translocase (39). 3HIA-carnitine is thought to be either directly deacylated by a hydrolase to 3HIA or to undergo a second CoA exchange to again form 3-hydroxyisovaleryl CoA followed by release of 3HIA and free CoA by a thioesterase.}}</ref>}}| group="note"}}}}}}<!--End of reference tooltip-based annotation-->
}}<!-- END OF ANNOTATED IMAGE TEMPLATE--><noinclude>

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