Acetyl-CoA carboxylase 2

Function

Mitochondrial enzyme that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA and plays a central role in fatty acid metabolism. Catalyzes a 2 steps reaction starting with the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain followed by the transfer of the carboxyl group from carboxylated biotin to acetyl-CoA. Through the production of malonyl-CoA that allosterically inhibits carnitine palmitoyltransferase 1 at the mitochondria, negatively regulates fatty acid oxidation (By similarity). Together with its cytosolic isozyme ACACA, which is involved in de novo fatty acid biosynthesis, promotes lipid storage (By similarity).

Classification

Family (Pfam)

PF08326 ACC_central, PF21385 ACCA_BT, PF02785 Biotin_carb_C, PF00289 Biotin_carb_N, PF00364 Biotin_lipoyl, PF01039 Carboxyl_trans, PF02786 CPSase_L_D2

InterPro

ACCA, ACCA_BT, AcCoA_carboxyl_beta, AcCoA_COase_cen, ATP-grasp, ATP_grasp_subdomain_1, BC-like_N, Biotin_carboxylation_dom, Biotin_COase_C, Biotin_lipoyl, ClpP/crotonase-like_dom_sf, COA_CT_C, COA_CT_N, CPAse_ATP-bd, PreATP-grasp_dom_sf, Rudment_hybrid_motif, Single_hybrid_motif

Functional cluster

Mixed Regulatory & Membrane Proteins

Experimental structures · PDB · 11

• 2DN8 NMR
• 2HJW X-ray 2.50A
• 2KCC NMR
• 3FF6 X-ray 3.19A
• 3GID X-ray 2.30A
• 3GLK X-ray 2.10A
• 3JRW X-ray 2.60A
• 3JRX X-ray 2.50A
• 3TDC X-ray 2.41A
• 4HQ6 X-ray 2.70A
• 5KKN X-ray 2.60A

A predicted model is available from AlphaFold.

Gene Ontology · 19

• GO:0005829 cytosol
• GO:0005741 mitochondrial outer membrane
• GO:0005739 mitochondrion
• GO:0005634 nucleus
• GO:0003989 acetyl-CoA carboxylase activity
• GO:0005524 ATP binding
• GO:0042802 identical protein binding
• GO:0046872 metal ion binding
• GO:0006084 acetyl-CoA metabolic process
• GO:0097009 energy homeostasis
• GO:0006633 fatty acid biosynthetic process
• GO:0055089 fatty acid homeostasis
• GO:2001295 malonyl-CoA biosynthetic process
• GO:0031999 negative regulation of fatty acid beta-oxidation
• GO:0060421 positive regulation of heart growth
• GO:0010884 positive regulation of lipid storage
• GO:0051289 protein homotetramerization
• GO:0010906 regulation of glucose metabolic process
• GO:0031667 response to nutrient levels

Drugs targeting this protein · 4

• PF-05175157 inhibitor
• FIRSOCOSTAT negative allosteric modulator
• OLUMACOSTAT GLASARETIL inhibitor
• CLESACOSTAT inhibitor

Related proteins · sequence + function similarity

• Acetyl-CoA carboxylase 2 0.96
• Acetyl-CoA carboxylase 0.80
• Acetyl-CoA carboxylase 1 0.79
• Acetyl-CoA carboxylase 1 0.78
• Acetyl-CoA carboxylase 1 0.78
• Acetyl-CoA carboxylase 1 0.78
• Acetyl-CoA carboxylase 1 0.78
• Acetyl-CoA carboxylase 0.72
• Acetyl-CoA carboxylase 0.70
• Acetyl-CoA carboxylase dmxL1 0.69
• Acetyl-CoA carboxylase 1 0.66
• Acetyl-CoA carboxylase 1 0.66

Co-cited proteins · studied together in the literature

• Acetyl-CoA carboxylase 2 1 shared papers
• Mid1-interacting protein 1 2 shared papers
• Acetyl-CoA carboxylase 1 2 shared papers
• Acetyl-CoA carboxylase 1 2 shared papers
• Thyroid hormone-inducible hepatic protein 1 shared papers
• Acyl-coenzyme A thioesterase 9, mitochondrial 1 shared papers
• ATP-binding cassette sub-family B member 5 1 shared papers
• Actin-binding LIM protein 2 1 shared papers
• Disintegrin and metalloproteinase domain-containing protein 11 1 shared papers
• Rho GTPase-activating protein SYDE1 1 shared papers
• Glucosylceramide transporter ABCA12 1 shared papers
• Disintegrin and metalloproteinase domain-containing protein 19 1 shared papers

Literature · 18 cited papers

• Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. Proc. Natl. Acad. Sci. U.S.A. · 2016
• An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
• Crystal structure of Spot 14, a modulator of fatty acid synthesis. Proc. Natl. Acad. Sci. U.S.A. · 2010
• Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis. Proc. Natl. Acad. Sci. U.S.A. · 2010
• Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK. Biochem. Biophys. Res. Commun. · 2010
• The human ACC2 CT-domain C-terminus is required for full functionality and has a novel twist. Acta Crystallogr. D · 2009
• Characterization of recombinant human acetyl-CoA carboxylase-2 steady-state kinetics. Biochim. Biophys. Acta · 2009
• ACC2 is expressed at high levels in human white adipose and has an isoform with a novel N-terminus. PLoS ONE · 2009
• Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science · 2008
• A quantitative atlas of mitotic phosphorylation. Proc. Natl. Acad. Sci. U.S.A. · 2008
• Biotinoyl domain of human acetyl-CoA carboxylase: Structural insights into the carboxyl transfer mechanism. Proteins · 2008
• Crystal structure of the biotin carboxylase domain of human acetyl-CoA carboxylase 2. Proteins · 2008
• … and 6 more in the literature graph