Reactome | ACLY tetramer binds ETC-1002-CoA

ACLY tetramer binds ETC-1002-CoA

Stable Identifier

R-HSA-9734540

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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Cytosolic ATP-citrate synthase (ACLY) is an important enzyme with significant effects on fatty acid and cholesterol metabolism. It is highly expressed in lipogenic tissues such as the liver and white adipose tissue and links energy metabolism from carbohydrates to the production of fatty acids through catalyzing acetyl CoA synthesis, the fundamental substrate for the biosynthesis of both fatty acids and cholesterol. Elevated LDL-C levels are a well-established risk factor for atherosclerotic cardiovascular disease (ACSVD) and hypercholesterolemia. Its crucial role in lipid biosynthesis makes ACLY a potential target for lipid-lowering intervention.

Bempedoic acid (ETC-1002) is first-in-class adenosine triphosphate-citrate lyase (ACLY) inhibitor used once a day for reducing LDL cholesterol levels in statin-refractory patients. ETC-1002 itself is a prodrug, which is converted to an active metabolite (ETC-1002–CoA) by endogenous liver acyl-CoA synthetase activity (Pinkosky et al. 2016), which then inhibits ACLY (Pinkosky et al. 2013, 2016).

By inhibiting cholesterol synthesis in the liver, ETC-1002 induces upregulation of the LDL receptor and stimulates the uptake of LDL particles by the liver, which contributes to reductions of LDL-C levels in the blood. Also, because the prodrug is converted to the active drug specifically in the liver, this may avoid potential adverse muscle effects as seen with cholesterol inhibition by statins in muscle (Susekov et al. 2021).

Literature References

PubMed ID	Title	Journal	Year
23118444	AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism Pinkosky, SL, Filippov, S, Srivastava, RA, Hanselman, JC, Bradshaw, CD, Hurley, TR, Cramer, CT, Spahr, MA, Brant, AF, Houghton, JL, Baker, C, Naples, M, Adeli, K, Newton, RS	J Lipid Res	2013
27892461	Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis Pinkosky, SL, Newton, RS, Day, EA, Ford, RJ, Lhotak, S, Austin, RC, Birch, CM, Smith, BK, Filippov, S, Groot, PHE, Steinberg, GR, Lalwani, ND	Nat Commun	2016