Literature summary for 2.3.3.8 extracted from

Wei, J.; Leit, S.; Kuai, J.; Therrien, E.; Rafi, S.; Harwood, H.J.; DeLaBarre, B.; Tong, L.
An allosteric mechanism for potent inhibition of human ATP-citrate lyase (2019), Nature, 568, 566-570 .

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Application

Application	Comment	Organism
drug development	the enzyme is a target for anticancer drugs, because many cancer cells depend on its activity for proliferation. ACLY is also a target against dyslipidaemia and hepatic steatosis. Under physiological conditions, citrate carries three negative charges and establishes predominantly hydrophilic and ionic interactions with the enzyme in its binding site, which would not be optimal for drug discovery. The extensive conformational changes observed here reveal a hydrophobic cavity in the core of the citrate domain allowing the high-affinity binding of more hydrophobic and drug-like molecules such as NDI-091143. The allosteric site offers an attractive target for the development of ACLY inhibitors	Homo sapiens

Protein Variants

Protein Variants	Comment	Organism
D1026N	mutant enzyme has 2% activity compared to wild-type enzyme	Homo sapiens
H975A	mutant enzyme has 25% activity compared to wild-type enzyme	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
methyl 3-chloro-5-(N-(4,6-difluoro-[1,1'-biphenyl]-3-yl)sulfamoyl)-4-hydroxybenzoate	i.e. NDI-091143, the structure of the full-length human ACLY homo-tetramer in complex NDI-091143 is determined by cryo-electron microscopy. The compound is located in an allosteric, mostly hydrophobic cavity next to the citrate-binding site, and requires extensive conformational changes in the enzyme that indirectly disrupt citrate binding	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
ATP + citrate + CoA	Homo sapiens	-	ADP + phosphate + acetyl-CoA + oxaloacetate	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P53396	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
ATP + citrate + CoA	-	Homo sapiens	ADP + phosphate + acetyl-CoA + oxaloacetate	-	?

Subunits

Subunits	Comment	Organism
tetramer	-	Homo sapiens

Synonyms

Synonyms	Comment	Organism
ACLY	-	Homo sapiens

General Information

General Information	Comment	Organism
metabolism	ATP-citrate lyase is a central metabolic enzyme. The acetyl-CoA product is crucial for the metabolism of fatty acids, the biosynthesis of cholesterol, and the acetylation and prenylation of proteins	Homo sapiens

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Release 2023.1 (January 2023)