HMG-CoA

HMG-CoA
Names
	IUPAC name (9R,21S)-1-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)tetrahydrofuran-2-yl]-3,5,9,21-tetrahydroxy-8,8,21-trimethyl-10,14,19-trioxo-2,4,6-trioxa-18-thia-11,15-diaza-3,5-diphosphatricosan-23-oic acid 3,5-dioxide
Identifiers
CAS Number	1553-55-5 ;
3D model (JSmol)	Interactive image;
ChEBI	CHEBI:61659 ;
ChemSpider	392859 ;
ECHA InfoCard	100.014.820
IUPHAR/BPS	3040;
MeSH	HMG-CoA
PubChem CID	445127;
CompTox Dashboard (EPA)	DTXSID00935181 ;
	InChI InChI=1S/C27H44N7O20P3S/c1-26(2,21(40)24(41)30-5-4-15(35)29-6-7-58-17(38)9-27(3,42)8-16(36)37)11-51-57(48,49)54-56(46,47)50-10-14-20(53-55(43,44)45)19(39)25(52-14)34-13-33-18-22(28)31-12-32-23(18)34/h12-14,19-21,25,39-40,42H,4-11H2,1-3H3,(H,29,35)(H,30,41)(H,36,37)(H,46,47)(H,48,49)(H2,28,31,32)(H2,43,44,45)/t14-,19-,20-,21+,25-,27+/m1/s1 Key: CABVTRNMFUVUDM-VRHQGPGLSA-N ; InChI=1/C27H44N7O20P3S/c1-26(2,21(40)24(41)30-5-4-15(35)29-6-7-58-17(38)9-27(3,42)8-16(36)37)11-51-57(48,49)54-56(46,47)50-10-14-20(53-55(43,44)45)19(39)25(52-14)34-13-33-18-22(28)31-12-32-23(18)34/h12-14,19-21,25,39-40,42H,4-11H2,1-3H3,(H,29,35)(H,30,41)(H,36,37)(H,46,47)(H,48,49)(H2,28,31,32)(H2,43,44,45)/t14-,19-,20-,21+,25-,27+/m1/s1 Key: CABVTRNMFUVUDM-VRHQGPGLBX;
	SMILES O=C(O)C[C@@](O)(C)CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n2cnc1c(ncnc12)N)[C@H](O)[C@@H]3OP(=O)(O)O;
Properties
Chemical formula	C27H44N7O20P3S
Molar mass	911.661 g/mol
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
	verify (what is ?)
	Infobox references

β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl-CoA, is an intermediate in the mevalonate and ketogenesis pathways. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase. The research of Minor J. Coon and Bimal Kumar Bachhawat in the 1950s at University of Illinois led to its discovery.[1][2]

HMG-CoA is a metabolic intermediate in the metabolism of the branched-chain amino acids, which include leucine, isoleucine, and valine.[3] Its immediate precursors are β-methylglutaconyl-CoA (MG-CoA) and β-hydroxy β-methylbutyryl-CoA (HMB-CoA).[4][5][6]

Biosynthesis

Leucine metabolism in humans

L-Leucine

Branched-chain amino
acid aminotransferase

α-Ketoglutarate

Glutamate

Alanine

Pyruvate

Muscle: α-Ketoisocaproate (α-KIC)

Liver: α-Ketoisocaproate (α-KIC)

Branched-chain α-ketoacid
dehydrogenase (mitochondria)

KIC-dioxygenase
(cytosol)

Isovaleryl-CoA

β-Hydroxy
β-methylbutyrate
(HMB)

Excreted
in urine
(10–40%)

HMB-CoA

β-Hydroxy β-methylglutaryl-CoA
(HMG-CoA)

β-Methylcrotonyl-CoA
(MC-CoA)

β-Methylglutaconyl-CoA
(MG-CoA)

CO₂

O₂

CO₂

H₂O

CO₂

H₂O

(liver)
HMG-CoA
lyase

Enoyl-CoA hydratase

Isovaleryl-CoA
dehydrogenase

MC-CoA
carboxylase

MG-CoA
hydratase

HMG-CoA
reductase

HMG-CoA
synthase

β-Hydroxybutyrate
dehydrogenase

Mevalonate
pathway

Unknown
enzyme

Human metabolic pathway for HMB and isovaleryl-CoA relative to L-leucine.[4][5][6] Of the two major pathways, L-leucine is mostly metabolized into isovaleryl-CoA, while only about 5% is metabolized into HMB.[4][5][6]

Mevalonate pathway

Mevalonate synthesis begins with the beta-ketothiolase-catalyzed Claisen condensation of two molecules of acetyl-CoA to produce acetoacetyl CoA. The following reaction involves the joining of acetyl-CoA and acetoacetyl-CoA to form HMG-CoA, a process catalyzed by HMG-CoA synthase.[7]

In the final step of mevalonate biosynthesis, HMG-CoA reductase, an NADPH-dependent oxidoreductase, catalyzes the conversion of HMG-CoA into mevalonate, which is the primary regulatory point in this pathway. Mevalonate serves as the precursor to isoprenoid groups that are incorporated into a wide variety of end-products, including cholesterol in humans.[8]

Mevalonate pathway

Ketogenesis pathway

HMG-CoA lyase breaks it into acetyl CoA and acetoacetate.

Ketogenesis

gollark: It's currently generating a regex for `hyperbee`.

gollark: `b(e(sä|äs)|s(eä|äe)|ä(es|se))|e(b(sä|äs)|s(bä|äb)|ä(bs|sb))|s(b(eä|äe)|e(bä|äb)|ä(be|eb))|ä(b(es|se)|e(bs|sb)|s(be|eb))`

gollark: Want another?

gollark: See, this is perfect and without flaw except that the time requirement to make the regex seems to increase exponentially due to greenery.

gollark: Here you go, `b(d(e(e(io|oi)|i(eo|oe)|o(ei|ie))|i(e(eo|oe)|oe{2})|o(e(ei|ie)|ie{2}))|e(d(e(io|oi)|i(eo|oe)|o(ei|ie))|e(d(io|oi)|i(do|od)|o(di|id))|i(d(eo|oe)|e(do|od)|o(de|ed))|o(d(ei|ie)|e(di|id)|i(de|ed)))|i(d(e(eo|oe)|oe{2})|e(d(eo|oe)|e(do|od)|o(de|ed))|o(de{2}|e(de|ed)))|o(d(e(ei|ie)|ie{2})|e(d(ei|ie)|e(di|id)|i(de|ed))|i(de{2}|e(de|ed))))|d(b(e(e(io|oi)|i(eo|oe)|o(ei|ie))|i(e(eo|oe)|oe{2})|o(e(ei|ie)|ie{2}))|e(b(e(io|oi)|i(eo|oe)|o(ei|ie))|e(b(io|oi)|i(bo|ob)|o(bi|ib))|i(b(eo|oe)|e(bo|ob)|o(be|eb))|o(b(ei|ie)|e(bi|ib)|i(be|eb)))|i(b(e(eo|oe)|oe{2})|e(b(eo|oe)|e(bo|ob)|o(be|eb))|o(be{2}|e(be|eb)))|o(b(e(ei|ie)|ie{2})|e(b(ei|ie)|e(bi|ib)|i(be|eb))|i(be{2}|e(be|eb))))|e(b(d(e(io|oi)|i(eo|oe)|o(ei|ie))|e(d(io|oi)|i(do|od)|o(di|id))|i(d(eo|oe)|e(do|od)|o(de|ed))|o(d(ei|ie)|e(di|id)|i(de|ed)))|d(b(e(io|oi)|i(eo|oe)|o(ei|ie))|e(b(io|oi)|i(bo|ob)|o(bi|ib))|i(b(eo|oe)|e(bo|ob)|o(be|eb))|o(b(ei|ie)|e(bi|ib)|i(be|eb)))|e(b(d(io|oi)|i(do|od)|o(di|id))|d(b(io|oi)|i(bo|ob)|o(bi|ib))|i(b(do|od)|d(bo|ob)|o(bd|db))|o(b(di|id)|d(bi|ib)|i(bd|db)))|i(b(d(eo|oe)|e(do|od)|o(de|ed))|d(b(eo|oe)|e(bo|ob)|o(be|eb))|e(b(do|od)|d(bo|ob)|o(bd|db))|o(b(de|ed)|d(be|eb)|e(bd|db)))|o(b(d(ei|ie)|e(di|id)|i(de|ed))|d(b(ei|ie)|e(bi|ib)|i(be|eb))|e(b(di|id)|d(bi|ib)|i(bd|db))|i(b(de|ed)|d(be|eb)|e(bd|db))))|i(b(d(e(eo|oe)|oe{2})|e(d(eo|oe)|e(do|od)|o(de|ed))|o(de{2}|e(de|ed)))|d(b(e(eo|oe)|oe{2})|e(b(eo|oe)|e(bo|ob)|o(be|eb))|o(be{2}|e(be|eb)))|e(b(d(eo|oe)|e(do|od)|o(de|ed))|d(b(eo|oe)|e(bo|ob)|o(be|eb))|e(b(do|od)|d(bo|ob)|o(bd|db))|o(b(de|ed)|d(be|eb)|e(bd|db)))|o(b(de{2}|e(de|ed))|d(be{2}|e(be|eb))|e(b(de|ed)|d(be|eb)|e(bd|db))))|o(b(d(e(ei|ie)|ie{2})|e(d(ei|ie)|e(di|id)|i(de|ed))|i(de{2}|e(de|ed)))|d(b(e(ei|ie)|ie{2})|e(b(ei|ie)|e(bi|ib)|i(be|eb))|i(be{2}|e(be|eb)))|e(b(d(ei|ie)|e(di|id)|i(de|ed))|d(b(ei|ie)|e(bi|ib)|i(be|eb))|e(b(di|id)|d(bi|ib)|i(bd|db))|i(b(de|ed)|d(be|eb)|e(bd|db)))|i(b(de{2}|e(de|ed))|d(be{2}|e(be|eb))|e(b(de|ed)|d(be|eb)|e(bd|db))))` matches all anagrams of `beeoid`.

References

Sarkar DP (2015). "Classics in Indian Medicine" (PDF). The National Medical Journal of India (28): 3. Archived from the original (PDF) on 2016-05-31.
Surolia A (1997). "An outstanding scientist and a splendid human being" (PDF). Glycobiology. 7 (4): v–ix. doi:10.1093/glycob/7.4.453.
"Valine, leucine and isoleucine degradation - Reference pathway". Kyoto Encyclopedia of Genes and Genomes. Kanehisa Laboratories. 27 January 2016. Retrieved 1 February 2018.
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.
Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH (April 2011). "HMB supplementation: clinical and athletic performance-related effects and mechanisms of action". Amino Acids. 40 (4): 1015–1025. doi:10.1007/s00726-010-0678-0. PMID 20607321. 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).
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
Garrett RH (2013). Biochemistry. Cengage Learning. p. 856. ISBN 978-1-305-57720-6.
Haines BE, Steussy CN, Stauffacher CV, Wiest O (October 2012). "Molecular modeling of the reaction pathway and hydride transfer reactions of HMG-CoA reductase". Biochemistry. 51 (40): 7983–95. doi:10.1021/bi3008593. PMC 3522576. PMID 22971202.

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[Classics_in_Indian_Medicine-1] Sarkar DP (2015). "Classics in Indian Medicine" (PDF). The National Medical Journal of India (28): 3. Archived from the original (PDF) on 2016-05-31.

[An_outstanding_scientist_and_a_splendid_human_being-2] Surolia A (1997). "An outstanding scientist and a splendid human being" (PDF). Glycobiology. 7 (4): v–ix. doi:10.1093/glycob/7.4.453.

[HMG_biosynthesis-3] "Valine, leucine and isoleucine degradation - Reference pathway". Kyoto Encyclopedia of Genes and Genomes. Kanehisa Laboratories. 27 January 2016. Retrieved 1 February 2018.

[ISSN_position_stand_2013-4] 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.

[HMB_athletic_performance-related_effects_2011_review-5] Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH (April 2011). "HMB supplementation: clinical and athletic performance-related effects and mechanisms of action". Amino Acids. 40 (4): 1015–1025. doi:10.1007/s00726-010-0678-0. PMID 20607321. 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).

[Leucine_metabolism-6] 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] Garrett RH (2013). Biochemistry. Cengage Learning. p. 856. ISBN 978-1-305-57720-6.

[8] Haines BE, Steussy CN, Stauffacher CV, Wiest O (October 2012). "Molecular modeling of the reaction pathway and hydride transfer reactions of HMG-CoA reductase". Biochemistry. 51 (40): 7983–95. doi:10.1021/bi3008593. PMC 3522576. PMID 22971202.

HMG-CoA

Biosynthesis

Mevalonate pathway

Ketogenesis pathway

See also

References