ACACA and Associated Diseases
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Overview of ACC-alpha
Acetyl-CoA carboxylase (ACC) refers to a multifunctional enzyme system that catalyzes the carboxylation of acetyl-CoA for the production of malonyl-CoA. There are two forms of ACCs in mammalian cells, alpha and beta, encoded by the ACACA and ACACB genes, respectively. There are three important functional domains for ACC-alpha, which include a biotin carboxylase (BC) domain, a carboxyl transferase (CT) domain, as well as a biotin carboxyl carrier protein (BCCP) domain. Due to the wider spatial dimension, the BC domain and CT domain of the same ACC-alpha molecule is difficult to bind. In this case, the homodimeric form of ACC-alpha molecules can be linked to the cascade of acetyl-CoA carboxylation. Regulation of ACC-alpha homodimer formation will be an important mechanism controlling ACC-alpha acetyl-CoA carboxylation activity.
Fig.1 Structure of ACC1 and function of three main domains. (Wang, 2022)
Distribution and Functions of ACC-alpha
ACC-alpha distributes widely in different types of organs and tissues. ACC-alpha is located in the cytosol and is responsible for converting cytosolic acetyl-CoA to malonyl-CoA for fatty acid synthesis. As the first rate-limiting enzyme with a central role in fatty acid synthesis, ACC-alpha is the hub of the fatty acid synthesis-related metabolic network. Studies have shown that the ACC-alpha inhibitor can completely block hepatic de novo lipogenesis. In cancer cells, inhibition of ACC-alpha by Soraphen A renders cells susceptible to oxidative stress and reduces cytoplasmic membrane fluidity. In addition to metabolic functions, ACC-alpha can also regulate protein acetylation by manipulating the availability of acetyl-CoA in cells.
Dysregulation of ACC-alpha in Human Diseases
Fatty acid synthesis is involved in multiple biological processes in life activities. Therefore, dysregulation of ACC-alpha-mediated fatty acid synthesis predisposes the development of diseases, especially cancer and metabolic diseases. When tumor cells are subjected to metabolic stress, ACC-alpha can mediate AMPK-sensed metabolic stress and downstream metabolic reprogramming. Under special conditions, the AMPK/ACC signaling pathway can alternately regulate tumor cell proliferation by maintaining NADPH homeostasis. In summary, ACC-alpha has served as a potential therapeutic target against various diseases, such as cancers and metabolic diseases.
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Reference
- Wang, Y.; et al. Acetyl-CoA carboxylases and diseases. Frontiers in Oncology. 2022, 12: 836058.
