Acetyl-CoA Carboxylase

Structure

acetylcoa_carboxylase.jpg
Fig. 1. 2.8 Å Crystal Structure of CT domain of acetyl-CoA carboxylase in S. cerevisiae. Yu, L. P. C. et al. (2010). PNAS. 107(51), 22072-22077

ACC consists of a carboxyltransferase (CT) domain and a biotin carboxyl carrier protein (BCCP) domain. As shown in figure 1, the CT domain contains two N-terminal monomers (cyan and magenta) and a C-terminal dimer (yellow and green). Its catalytic site for carboxyl transferase activty is located between the cyan and green subunits. Circled in figure 1 is the location of the acetyl-CoA substrate.[1]

Function

ACC serves as the critical first step in lipogenesis. It catalyzes the irreversible carboxylation of acetyl-CoA to malonyl-CoA using biotin in two steps as shown in figure 2. The initial step involves usage of a carbonyl phosphate for the carboxylation of a biotin moiety that is covalently bonded ACC's BCCP domain. The second step involves usage of the carboxylated biotin to carboxylate acetyl-CoA in the CT domain active site to form malonyl-CoA.[2]








ACC_Mech.jpg
Fig. 2. Electron Pushing Model of Acetyl-CoA Carboxylase's Catalytic Activity. Drawn by Tennison Yu.



Regulation

ACC is regulated by long term and short term mechanisms. In the long term, ACC expression can be downregulated at the genetic level by mRNA fragments. However, ACC has a relatively long half-life (60h). Thus the pre-existing ACC must regulated using short-term mechanisms. It can be allosterically regulated by cellular metabolites such as upregulation by citrate and downregulation by palmitoyl-CoA. It can also be covalently modified via phosphorylation by kinases such as PKA. For ACC, phosphorylation leads to deactivation while dephosphorylation leads to activation.[3]

Relevance to Lipolysis

Malonyl-CoA serves to inhibit CPT1 which plays a role in fat oxidation.[4] Lowering the activty of ACC by regulation would thus lead to less malonyl-CoA and less inhibition of carnitine acyltransferases.

Pathway 2
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  1. ^ Yu, L.P.C., Kim, Y.S., and Tong L., (2010). PNAS. 107(51), 22072-22077
  2. ^ Lee, C.K., Cheong, H.K., Ryu, K.S., Lee, J.I., Lee, W., Jeon, Y.H., and Cheong, C. (2008). Protein Structure, Function, and Bioinformatics. 72(2), 613-624
  3. ^ Kim, K.H., Lopez-Casillas, F., Bai, D.H., Luo, X., and Pape, M.E. (1989). The FASEB Journal. 3, 2250-2256
  4. ^ Hursel, R., and Westerterp-Plantegnga, M.S. (2010). International Journal of Obesity. 34, 659-669