• Title, Summary, Keyword: acetyl CoA carboxylase

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Hormonal Regulation of Acetyl-CoA Carboxylase Promoter I Activity in Rat Primary Hepatocytes (흰쥐의 간세포에서 호르몬에 의한 Acetyl-CoA Carboxylase Promoter I Activity 조절에 대한 연구)

  • 이막순;양정례;김윤정;김영화;김양하
    • Journal of Nutrition and Health
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    • v.35 no.2
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    • pp.207-212
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    • 2002
  • Acetyl-CoA carboxylase (ACC) is the enzyme that controls no devo fatty acid biogynthesis, and this enzyme catalyzes the carboxylation pathway of acetyl-CoA to malonyl-CoA. Acetyl-CoA carboxylase gene expression was regulated by nutritional and hormonal status. The present study was performed to identify the regulation mechanism of ACC gene promoter I. The fragments of ACC promoter I -1.2-kb region wert recombined to pGL3-Basic vector with luciferase as a reporter gene. The primary hepatocytes from the rat were used to investigate the hormonal regulation of ACC promoter I activity. ACC PI (-1.2)/Luc plasmid was trtransferred into primary hepatocytes using lipofectin. Activity of luciferase was increased two-fold by 10-9M, three-fold by 10-8M, 10-6M, 3.5-fold by 10-6M, and 4.5-fold by 10-7M insulin treatment, respectively. In the presence of dexamethasone (1 $\mu$M), the effects of insulin increased about 1.5-fold, showing the additional effects of dexamethasone. Moreover, the activity of luciferase increased with insulin+dexamethasone, insulin+T3, dexamethasone+T3, and dexamethasone+insulin+T3 treatment approximately 6-, 4-, 6.5-, and 10-fold, respectively. Therefore it can be postulated that 1) these hormones coordinately regulate acetyl-CoA caroxylase gene expression via regulation of promoter activity, 2) the -1.2-kb region of ACC promoter I may have the response element sequences for insulin, dexamethasone, and T3.

Cloning of Acetyl CoA Carboxylase (fabE) in Escherichia coli (대장균의 acetyl CoA carboxylase유전자의 클로닝)

  • Park, Wan;Song, Bang-Ho;Hong, Soon-Duk
    • Microbiology and Biotechnology Letters
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    • v.14 no.2
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    • pp.181-186
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    • 1986
  • A defective lambda transducing phase carrying acetyl CoA carboxylase gene (fabE) from Escherichia coli chromosome (72 min on the current linkage map) has been isolated. A restriction map of the chromosomal region from defective transducing phage was established by digestion with combination of the restriction enzymes. No cleavage site for the enzyme EcoRI was found in this region. Restriction fragments were cloned from defective transducing phage into high copy number plasmid vector pACYC184 to generate hybrid plasmids which were capable of complementation of fabE temperature sensitive mutation. We show here that the fabE gene is located on a 3.4 megadalton Bam HI-SalI fragment with a HindIII site, which lies within the 7.4 megadalton BglIIfragment, by complementation analysis.

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Structural Insights into the Regulation of ACC2 by Citrate

  • Kwon, Seong Jung;Cho, Yong Soon;Heo, Yong-Seok
    • Bulletin of the Korean Chemical Society
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    • v.34 no.2
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    • pp.565-568
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    • 2013
  • Acetyl-CoA carboxylases (ACCs) play critical roles in fatty acid synthesis and oxidation by the catalytic activity of the carboxylation of acetyl-CoA to malonyl-CoA. It is known that ACCs are inactivated through reversible phosphorylation by AMP-activated protein kinase (AMPK) and allosterically activated by citrate. Here, we determined the crystal structures of biotin carboxylase (BC) domain of human ACC2 phosphorylated by AMPK in the presence of citrate in order to elucidate the activation mechanism by citrate. This structure shows that phosphorylated Ser222 is released from the dimer interface, and thereby facilitating the dimerization or oligomerization of the BC domain allosterically. This structural explanation is coincident with the experimental result that the phosphorylated Ser222 was dephosphorylated more easily by protein phosphatase 2A (PP2A) as the citrate concentration increases.

The effective model of the human Acetyl-CoA Carboxylase inhibition by aromatic-structure inhibitors

  • Minh, Nguyen Truong Cong;Thanh, Bui Tho;Truong, Le Xuan;Suong, Nguyen Thi Bang;Thao, Le Thi Xuan
    • Journal of IKEEE
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    • v.21 no.3
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    • pp.309-319
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    • 2017
  • The research investigates the inhibition of fatty acid biosynthesis of the human Acetyl-CoA Carboxylase enzyme by the aromatic-structure inhibitors (also known as ligands) containing variables of substituents, contributing an important role in the treatment of fatty-acid metabolic syndrome expressed by the group of cardiovascular risk factors increasing the incidence of coronary heart disease and type-2 diabetes. The effective interoperability between ligand and enzyme is characterized by a 50% concentration of enzyme inhibitor ($IC_{50}$) which was determined by experiment, and the factor of geometry structure of the ligands which are modeled by quantum mechanical methods using HyperChem 8.0.10 and Gaussian 09W softwares, combining with the calculation of quantum chemical and chemico-physical structural parameters using HyperChem 8.0.10 and Padel Descriptor 2.21 softwares. The result data are processed with the combination of classical statistical methods and modern bioinformatics methods using the statistical softwares of Department of Pharmaceutical Technology - Jadavpur University - India and R v3.3.1 software in order to accomplish a model of the quantitative structure - activity relationship between aromatic-structure ligands inhibiting fatty acid biosynthesis of the human Acetyl-CoA Carboxylase.

Biotinoyl Domain of Human Acetyl-CoA Carboxylase;Structural Insights into the Carboxyl Transfer Mechanism

  • Lee, Chung-Kyung;Cheong, Hae-Kap;Ryu, Kyoung-Seok;Lee, Jae-Il;Jeon, Young-Ho;Cheong, Chae-Joon
    • Journal of the Korean Magnetic Resonance Society
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    • v.12 no.1
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    • pp.1-13
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    • 2008
  • Acetyl-CoA carboxylase (ACC) catalyzes the first step in fatty acid biosynthesis: the synthesis of malonyl-CoA from acetyl-CoA. As essential regulators of fatty acid biosynthesis and metabolism, ACCs are regarded as therapeutic targets for the treatment of metabolic diseases such as obesity, In ACC, the biotinoyl domain performs a critical function by transferring an activated carboxyl group from the biotin carboxylase domain to the carboxyl transferase domain, followed by carboxyl transfer to malonyl-CoA. Despite the intensive research on this enzyme, only the bacterial and yeast ACC structures are currently available, To explore the mechanism of ACC holoenzyme function, we determined the structure of the biotinoyl domain of human ACC2 and analyze its characteristics using NMR spectroscopy. The 3D structure of the hACC2 biotinoyl domain has a similar folding topology to the previously determined domains from E. coli and P. Shermanii, however, the 'thumb' structure is absent in the hACC2 biotinoyl domain. Observations of the NMR signals upon the biotinylation indicate that the biotin group of hACC2 does not affect the structure of the biotinoyl domain, while the biotin group for E. coli ACC interacts directly with the thumb residues that are not present in the hACC2 structure. These results imply that, in the E. coli ACC reaction, the biotin moiety carrying the carboxyl group from BC to CT can pause at the thumb of the BCCP domain. The human biotinoyl domain, however, lacks the thumb structure and does not have additional non-covalent interactions with the biotin moiety; thus, the flexible motion of the biotinylated lysine residue must underlie the "swinging arm" motion. This study provides insight into the mechanism of ACC holoenzyme function and supports the "swinging arm" model in human ACCs.

Molecular Docking to Acetyl-CoA Carboxylase of 2-(4-(6-chloro-2-benzoxazolyl)oxy)phenoxy-N-phenylpropionamide Analogues and Their Herbicidal Activity (Acetyl-CoA Carboxylase에 대한 2-(4-(6-chloro-2-benzoxazolyl)oxy)phenoxy-N-phenylpropionamide 유도체들의 분자 도킹과 제초활성)

  • Choi, Won-Seok;Sung, Nack-Do
    • The Korean Journal of Pesticide Science
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    • v.14 no.3
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    • pp.183-190
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    • 2010
  • To search the new potent herbicidal agents by receptor-based approach, the interactions between receptor and substrate molecules from molecular docking to acetyl-CoA carboxylase(PDB code: 3K8X) of 2-(4-(6-chloro-2-benzoxazolyl)oxy)phenoxy-N-phenylpropionamide analogues (1-38) as substrate molecules were performed and discussed quantitatively. The most of the substrate molecules were formated 2 H-bonds between carbonyl oxygen atom of the substrate molecules and the amino acid residues (Ala1627 and Ile1735) in binding site of acetyl-CoA carboxylase (ACCase). But, the substrate molecules such as $R_l$=Acetyl substituents (6 & P9) were formated 3 H-bonds between H-bond acceptors in the substrate molecules and the H-bond donors in three amino acid residues including the rest residue (Gly 1998). Therefore, the inhibitory activity factors of the substrate molecules against ACCase are due to the H-bonding characters that will be able to apply to the optimization of herbicidal agents.

Resveratrol Downregulates Acetyl-CoA Carboxylase $\alpha$ and Fatty Acid Synthase by AMPK-mediated Downregulation of mTOR in Breast Cancer Cells

  • Park, Sahng-Wook;Yoon, Sa-Rah;Moon, Jong-Seok;Park, Byeong-Woo;Kim, Kyung-Sup
    • Food Science and Biotechnology
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    • v.17 no.5
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    • pp.1047-1051
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    • 2008
  • Overexpression of HER2 in breast cancer cells is considered to induce the expression of acetyl-CoA carboxylase $\alpha$ (ACACA) and fatty acid synthase (FASN) through activation of mammalian target of rapamycin (mTOR) signaling pathway. Resveratrol, a red wine polyphenol, has been shown to induce apoptosis in several cancers by interfering in several signaling pathways. Present study elucidated the mechanism by which resveratrol downregulates ACACA and FASN in breast cancer cells. Resveratrol activated AMP-activated protein kinase (AMPK) and downregulated mTOR in BT-474 cells. These effects of resveratrol were mimicked by AICAR, an AMPK activator, and exogenously expressed constitutively active AMPK, while they were abolished by a dominant-negative mutant of AMPK. The downregulation of mTOR was not accompanied with changes in Akt, the upstream regulator of mTOR. These findings indicate that the downregulation of ACACA and FASN by resveratrol is mediated by the downregulation of mTOR signaling pathway via activation of AMPK.

Effects of Insulin on Acetyl-CoA Carboxylase in Bovine Mammary Secretory Cells

  • Kim, W.Y.;Ha, J.K.;Baldwin, R.L.
    • Asian-Australasian Journal of Animal Sciences
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    • v.10 no.1
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    • pp.134-140
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    • 1997
  • Objectives of this study were to determine effects of insulin on acetyl-CoA carboxylase (ACC) activity and correlate this activity with relative amounts of ACC in MAC-T cells. MAC-T cells were grown in Medium 199 supplemented with fetal bovine serum (5%), cortisol ($1{\mu}g/ml$), and insulin ($1{\mu}g/ml$). At confuluence, the cells were transferred to $100mm^2$ culture dishes coated with the extracelluar matrix. After 10 h of incubation, the media were replaced with media without fetal bovine serum and the concentration of insulin was lowered to 5 ng/ml. After 24 h, the media were changed to contain the varying concentrations of insulin and incubations continued for 48 h. The addition of insulin resulted in increases in the specific activity of ACC. The maximal effects of insulin on the ACC activity occurred at concentrations of insulin, 1,000 ng/ml. In contrast, the relative change in lactate dehydrogenase (LDH) activity in response to increasing insulin concentration was minimal as compared to the effects of insulin on ACC. Transblot and enhanced chemiluminescence (ECL) analysis indicated that the increase in ACC activity in MAC-T cells caused by insulin were due to actual increases in amounts of enzyme.

Effects of Mori Folium Ethanol Soluble Fraction on mRNA Expression of glucose transporters, acetyl-CoA carboxylase and leptin (상엽 에탄올가용분획의 글루코스전달체, acetyl-CoA 카복시라제 및 렙틴 mRNA 발현에 미치는 영향)

  • Ryu, Jeong-Wha;Yook, Chang-Soo;Chung, Sung-Hyun
    • YAKHAK HOEJI
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    • v.42 no.6
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    • pp.589-597
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    • 1998
  • Effects of Mori Folium Ethanol Soluble Fraction (MFESF) on mRNA expression of glucose transporters, acetyl-CoA carboxylase (ACC) and leptin were examined in db/db mice. 500 and 1000mg/kg dose for MFESF (designated by SY 500 and SY 1000, respectively) and 5mg/kg dose for acarbose were administered for 6 weeks. Quantitations of glucose transporters (GLUT-2 and GLUT-4), ACC and leptin mRNA were performed by RT-PCR and in vitro transcription with co-amplification of rat ${\beta}$-actin gene as an internal standard. Muscular GLUT-4 mRNA expression in MFESF-treated groups were increased dose dependently. On the other hand, MFESF caused the GLLT-4 and leptin mRNA expressions in adipose tissue to decrease dose dependently, which means that triglyceride synthesis in adipocytes might be decreased and consequently signals adipocytes to inhibit the synthesis and release of leptin. Hepatic ACC mRNA expression in MFESF-treated groups was also decreased. and this may result in lowering of serum triiglyceride level. In contrast, liver GLUT-2 mRNA expressions in MFESF-treated and acarbose groups were increased. Higher rate of glucose uptake into hepatocytes is known to inhibit a phosphoenolpyruvate carboxykinase (PEPCK)-catalyzed reaction, which is a rate-limiting step in gluconeogenesis.

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