ACLY

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ATP citrate lyase (ACLY) is an important enzyme involved in lipid biogenesis related to glucose metabolism. Generally, citrate is synthesized in the mitochondria and transported to the cytoplasm through the mitochondrial citrate carrier protein (encoded by the gene SLC25A1), where acetyl-CoA (AcCoA) and oxaloacetate are produced under the catalysis of ACLY. AcCoA is involved in many key life activities, including the synthesis of fatty acids, acetylcholine and cholesterol, and the acetylation of protein substrates including histones. At present, the high-resolution crystal structure of bacteria and human ACLY has been resolved, the conformation, substrate binding and catalytic process of ACLY can be characterized. These research advances will provide important clues for the development of new ACLY inhibitors and clarify the important role of ACLY in hyperlipidemia and various cancers.

Subcellular localization of ACLY gene

ACLY mainly exists in the cytoplasm of plants and animals. Some scholars have found ACLY activity in the chloroplasts of higher plants. In seaweeds, ACLY activity is only present in the cytoplasm, and there is no ACLY activity in the chromosomes. ACLY of young leaves of pea mainly exists in the cytoplasm.

Domain organization

Human ACLY contains a total of 1,101 amino acid residues and exists in the form of a 480 kDa homo-tetramer. It can be divided into six domains. Domain 1 can bind to CoA, the phosphorylation of His760 in domain 2 is the key site for the catalytic reaction, the ATP-grasp fold formed by domain 3 and 4 can bind ATP, and domain 5 is the citrate binding site. The amino acid sequence of the C-terminal domain has weak sequence homology with citrate synthase (CS).

Fig 1. Domain organization of human ACLY (Wei, J.; et al. 2019)

Structure of ACLY

The structure of human ACLY homo-tetramer is formed by the close combination of the α helix of the CS domain core, and the N-terminals of the four protomers are located at the periphery. Citryl-CoA is formed at the N-terminal of one protomer, and then transferred to the CCLY domain of another protomer to complete the catalytic reaction. This structure fully explains that ACLY can only be used in the tetramer. The reason that the entire reaction can be completed only under the form. This structure fully explains why ACLY can only complete the entire reaction in the form of a tetramer. The inhibitor NDI-091143 binds to the hydrophobic core of domain 5 (different from the citrate-binding site), this binding causes a conformational change in ACLY, which moves the side chain of Ile344 by about 6 Å and the guanidinium group of Arg379 by about 12 Å, making it unable to recognize citrate, thereby blocking the combination with citrate. The discovery of this mechanism greatly enhanced the ‘druggability’ of ACLY and provided a solid foundation for drug development for the treatment of cancer and metabolic disorders.  

Fig 2. Structure of the human ACLY tetramer in complex with NDI091143 and ADP (Wei, J.; et al.2019)

Inhibitor of ACLY

At present, the ACLY inhibitor Nexletol (bempedoic acid) has been approved by the FDA as a statin supplement therapy for patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH). The pharmaceutical company Esperion reported the test results of Nexletol in 2230 ASCVD and HeFH patients. The results showed that adding this drug to statins can significantly reduce the levels of LDL-cholesterol and the inflammation biomarker: C-reactive protein. Some analysts said that Nexletol may occupy up to a quarter of the cholesterol drug market and is expected to reach peak sales of $2 billion to $3 billion.

Conclusions

Since the discovery of ATP-citrate lyase, a large number of studies have been conducted on its enzymatic activity and function, and significant progress has been made. ATP-citrate lyase plays an important role in the organism. The production of acetyl-CoA under its action is the only way for the organism to produce acetyl-CoA. There is no other way to supplement the acetyl-CoA required by the organism. In recent years, some scholars have reported that it can improve crop resistance, ACLY is essential for plant growth and development.