5cte | pdb_00005cte

Humanized yeast ACC carboxyltransferase domain bound to 2,2-dimethylpropyl (1S)-1-methyl-8-[(7-methyl-1H-indazol-5-yl)carbonyl]-2,8-diazaspiro[4.5]decane-2-carboxylate

Structural highlights

5cte is a 2 chain structure with sequence from Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	57L, SO4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ACAC_YEAST Carries out three functions: biotin carboxyl carrier protein, biotin carboxylase and carboxyltransferase. Involved in the synthesis of very-long-chain fatty acid synthesis which is required to maintain a functional nuclear envelope. Required for acylation and vacuolar membrane association of VAC8 which is necessary to maintain a normal morphology of the vacuole.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30muM.

Discovery of spirocyclic-diamine inhibitors of mammalian acetyl CoA-carboxylase.,Kung DW, Griffith DA, Esler WP, Vajdos FF, Mathiowetz AM, Doran SD, Amor PA, Bagley SW, Banks T, Cabral S, Ford K, Garcia-Irizarry CN, Landis MS, Loomis K, McPherson K, Niosi M, Rockwell KL, Rose C, Smith AC, Southers JA, Tapley S, Tu M, Valentine JJ Bioorg Med Chem Lett. 2015 Sep 15. pii: S0960-894X(15)30067-6. doi:, 10.1016/j.bmcl.2015.09.035. PMID:26411795^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Mishina M, Roggenkamp R, Schweizer E. Yeast mutants defective in acetyl-coenzyme A carboxylase and biotin: apocarboxylase ligase. Eur J Biochem. 1980 Oct;111(1):79-87. PMID:6108218
↑ Roggenkamp R, Numa S, Schweizer E. Fatty acid-requiring mutant of Saccharomyces cerevisiae defective in acetyl-CoA carboxylase. Proc Natl Acad Sci U S A. 1980 Apr;77(4):1814-7. PMID:6103540
↑ Schneiter R, Hitomi M, Ivessa AS, Fasch EV, Kohlwein SD, Tartakoff AM. A yeast acetyl coenzyme A carboxylase mutant links very-long-chain fatty acid synthesis to the structure and function of the nuclear membrane-pore complex. Mol Cell Biol. 1996 Dec;16(12):7161-72. PMID:8943372
↑ Schneiter R, Guerra CE, Lampl M, Tatzer V, Zellnig G, Klein HL, Kohlwein SD. A novel cold-sensitive allele of the rate-limiting enzyme of fatty acid synthesis, acetyl coenzyme A carboxylase, affects the morphology of the yeast vacuole through acylation of Vac8p. Mol Cell Biol. 2000 May;20(9):2984-95. PMID:10757783
↑ Gao H, Sumanaweera N, Bailer SM, Stochaj U. Nuclear accumulation of the small GTPase Gsp1p depends on nucleoporins Nup133p, Rat2p/Nup120p, Nup85p, Nic96p, and the acetyl-CoA carboxylase Acc1p. J Biol Chem. 2003 Jul 11;278(28):25331-40. Epub 2003 May 1. PMID:12730220 doi:https://dx.doi.org/10.1074/jbc.M301607200
↑ Kung DW, Griffith DA, Esler WP, Vajdos FF, Mathiowetz AM, Doran SD, Amor PA, Bagley SW, Banks T, Cabral S, Ford K, Garcia-Irizarry CN, Landis MS, Loomis K, McPherson K, Niosi M, Rockwell KL, Rose C, Smith AC, Southers JA, Tapley S, Tu M, Valentine JJ. Discovery of spirocyclic-diamine inhibitors of mammalian acetyl CoA-carboxylase. Bioorg Med Chem Lett. 2015 Sep 15. pii: S0960-894X(15)30067-6. doi:, 10.1016/j.bmcl.2015.09.035. PMID:26411795 doi:https://dx.doi.org/10.1016/j.bmcl.2015.09.035

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[1] Mishina M, Roggenkamp R, Schweizer E. Yeast mutants defective in acetyl-coenzyme A carboxylase and biotin: apocarboxylase ligase. Eur J Biochem. 1980 Oct;111(1):79-87. PMID:6108218

[2] Roggenkamp R, Numa S, Schweizer E. Fatty acid-requiring mutant of Saccharomyces cerevisiae defective in acetyl-CoA carboxylase. Proc Natl Acad Sci U S A. 1980 Apr;77(4):1814-7. PMID:6103540

[3] Schneiter R, Hitomi M, Ivessa AS, Fasch EV, Kohlwein SD, Tartakoff AM. A yeast acetyl coenzyme A carboxylase mutant links very-long-chain fatty acid synthesis to the structure and function of the nuclear membrane-pore complex. Mol Cell Biol. 1996 Dec;16(12):7161-72. PMID:8943372

[4] Schneiter R, Guerra CE, Lampl M, Tatzer V, Zellnig G, Klein HL, Kohlwein SD. A novel cold-sensitive allele of the rate-limiting enzyme of fatty acid synthesis, acetyl coenzyme A carboxylase, affects the morphology of the yeast vacuole through acylation of Vac8p. Mol Cell Biol. 2000 May;20(9):2984-95. PMID:10757783

[5] Gao H, Sumanaweera N, Bailer SM, Stochaj U. Nuclear accumulation of the small GTPase Gsp1p depends on nucleoporins Nup133p, Rat2p/Nup120p, Nup85p, Nic96p, and the acetyl-CoA carboxylase Acc1p. J Biol Chem. 2003 Jul 11;278(28):25331-40. Epub 2003 May 1. PMID:12730220 doi:https://dx.doi.org/10.1074/jbc.M301607200

[6] Kung DW, Griffith DA, Esler WP, Vajdos FF, Mathiowetz AM, Doran SD, Amor PA, Bagley SW, Banks T, Cabral S, Ford K, Garcia-Irizarry CN, Landis MS, Loomis K, McPherson K, Niosi M, Rockwell KL, Rose C, Smith AC, Southers JA, Tapley S, Tu M, Valentine JJ. Discovery of spirocyclic-diamine inhibitors of mammalian acetyl CoA-carboxylase. Bioorg Med Chem Lett. 2015 Sep 15. pii: S0960-894X(15)30067-6. doi:, 10.1016/j.bmcl.2015.09.035. PMID:26411795 doi:https://dx.doi.org/10.1016/j.bmcl.2015.09.035

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5cte | pdb_00005cte

Humanized yeast ACC carboxyltransferase domain bound to 2,2-dimethylpropyl (1S)-1-methyl-8-[(7-methyl-1H-indazol-5-yl)carbonyl]-2,8-diazaspiro[4.5]decane-2-carboxylate

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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