Biology of microbes
Philip A. Geis in Cosmetic Microbiology, 2006
Synthesis of lipids. Fatty acid synthesis is catalyzed with fatty acid synthetase using acetyl-CoA and malonyl-CoA as the substrates and NADPH as the reductant. Malonyl-CoA comes from an ATP-driven carboxylation (addition of CO2) of acetyl-CoA that comes from glycolysis. Both acetate and malonate are transferred from coenzyme A to the sulfhydryl group of the acyl carrier protein (ACP) that carries the growing fatty acid chain during synthesis. The synthetase adds two carbons at a time to the carboxyl end of the growing fatty acid chain in a two-stage process. First, malonyl-ACP reacts with a fatty acyl-ACP and yields CO2 and a fatty acyl-ACP that is now two carbons longer. Glycerol can be esterified to fatty acids to result in phosphatidic acid and then to phospholipids that are essential to membrane function.
Primary Prevention of Type 2 Diabetes
Emmanuel C. Opara, Sam Dagogo-Jack in Nutrition and Diabetes, 2019
Acetyl-CoA, a product of glycolysis for the Krebs cycle, can be converted to malonyl CoA by the enzyme acetyl-CoA carboxylase (ACC). Malonyl-CoA is the activated two-carbon donor required for fatty acid synthesis. Malonyl-CoA also is a potent inhibitor of CPT-1, thereby blocking the delivery and oxidation of fatty acids in mitochondria. The result is accumulation of long-chain fatty acids in the cytosol and eventual lipotoxicity [14,15]. Glucose abundance also increases the formation of intracellular DAG. Thus, multiple metabolic pathways link intracellular glucose abundance (usually derived from carbohydrate consumption) to impaired fat oxidation, fatty acid synthesis, accumulation of long-chain fatty acids, risk of lipotoxicity, and insulin resistance. Among the potent interventions that have been demonstrated to ameliorate the pathological cellular and molecular processes leading to insulin resistance are caloric restriction (reduction of carbohydrate and fat intake), physical activity, and weight loss [16–24].
Bioactive Metabolites
Gokare A. Ravishankar, Ranga Rao Ambati in Handbook of Algal Technologies and Phytochemicals, 2019
Manipulating fatty acids synthesis is still in its infancy because of incomplete knowledge of the regulation of carbon partitioning and detailed fatty-acid synthesis and catabolism. For example, engineering the Fatty Acid Synthesis complex (FAS) has been done, leading to modified composition of fatty acids but not increased content (Blatti et al. 2012). Similarly, manipulation of expression of DGAT genes did not contribute to modifying lipid content (Deng et al. 2012; La Russa et al. 2012). Other targets include a multifunctional enzyme (lipase/phospholipase/acyltransferase) whose downregulation in P. tricornutum increased lipid content without affecting growth rate in the diatom Thalasossiera pseudonana (Trentacoste et al. 2013) (reviewed in Bellou et al 2014).
New insights into the metabolism of Th17 cells
Published in Immunological Medicine, 2023
Michihito Kono
Fatty acid oxidation is a mitochondrial aerobic process responsible for producing acetyl CoA from fatty acids. In contrast, fatty acid synthesis is the creation of fatty acids from acetyl CoA and Nicotinamide adenine dinucleotide phosphate (NADPH) [13]. Adenosine monophosphate-activated protein kinase (AMPK), a serine/threonine kinase, is a vital metabolic regulator that inhibits mTORC activity. AMPK-dependent phosphorylation of acetyl-CoA carboxylase 1 (ACC1) is the rate-limiting enzyme for fatty acid synthesis. ACC1 modulates the DNA binding of RORγt to target genes and enhances Th17 cell differentiation [79–81]. Cholesterol is synthesized from acetyl CoA by the hydroxymethylglutaryl-coenzyme A (HMG-CoA). Statin, an inhibitor of HMG-CoA reductase, reduces Th17 cell differentiation [82].
Acetyl-CoA carboxylase (ACC) as a therapeutic target for metabolic syndrome and recent developments in ACC1/2 inhibitors
Published in Expert Opinion on Investigational Drugs, 2019
Leyuan Chen, Yuqing Duan, Huiqiang Wei, Hongxin Ning, Changfen Bi, Ying Zhao, Yong Qin, Yiliang Li
The structure of most eukaryotic ACCs is a polypeptide containing three major domains, biotin carboxylase (BC), biotin-containing carboxyl carrier protein (BCCP), and carboxyltransferase (CT). In most prokaryotic organisms, ACC is an enzyme complex comprised of multiple subunits. There are two isoforms of ACC found in mammals. One is ACC1 (ACCα, 265 kDa) encoded by ACACA gene on chromosome 17q12, and the other is ACC2 (ACCβ, 275 kDa) encoded by ACACB gene on chromosome 12q23 [8–11]. In mammals, ACC1 and ACC2 are highly conserved. The main difference is that ACC2 is a mitochondria protein directed by its hydrophobic N-terminal leader sequence to the mitochondrial membrane, while ACC1 is a cytoplasmic protein [12]. In liver and adipose tissue, malonyl-CoA produced by ACC1 acts as a fatty acid synthesis unit, and further extends the carbon chain to form long-chain fatty acids under the action of fatty acid synthase. ACC2 is mainly expressed in tissues such as heart and skeletal muscle, and its catalyzed production of malonyl-CoA is an inhibitor of CPT-1 (Figure 1) [13]. Due to their different distributions, selective inhibition of ACC1 or AAC2 may bring different physiological changes [11].
Research progress of nanocarriers for gene therapy targeting abnormal glucose and lipid metabolism in tumors
Published in Drug Delivery, 2021
Xianhu Zeng, Zhipeng Li, Chunrong Zhu, Lisa Xu, Yong Sun, Shangcong Han
The synthesis of FAs is an essential cellular process that uses glutamine or glucose as building blocks (Rohrig & Schulze 2016; Min & Lee 2018). Citrate is a major intermediate product produced by the TCA cycle that produces FAs through the action of several key enzymes, such as ATP citrate lyase (ACLY) and fatty acid synthase (FASN) (Lee et al. 2015). ACLY converts citrate into acetyl-CoA, which is an important enzyme that can link carbohydrates and lipid metabolism by generating acetyl-CoA from citric acid, thereby achieving the biosynthesis of fatty acids (Feng et al. 2020). Acetyl-CoA carboxylase (ACC) catalyzes the formation of malonyl-CoA, which is an important substrate and key regulatory molecule for fatty acid synthesis in adipose tissue (Choosangtong et al. 2015). Adenosine monophosphate (AMP)-activated protein kinase phosphorylates and inhibits ACC, which indirectly inhibits the synthesis of fatty acid (Lepropre et al. 2018). FASN uses malonyl-CoA as a substrate to synthesize the final form of fatty acids. It has been found that FASN is associated with progression in a variety of cancers, and hence, it is an important target for cancer therapy (Jones & Infante 2015; Menendez & Lupu 2017).