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  • br Crystal structure ACLY protein is a homotetramer of

    2024-04-15


    Crystal structure ACLY protein is a homotetramer of four identical subunits [9]. Each polypeptide chain contains 1101 amino-acid residues [10]. The crystal structure of full-length ACLY protein is yet unresolved. However, Sun et al. recently succeeded in crystallizing chymotrypsin-truncated human ACLY [11], [12]. X-ray crystallography data obtained from these studies revealed about two-third of the structure of ACLY. The binding sites for both citrate and ATP have also been identified [11]. More recently the structure for the amino-terminal portion of the enzyme containing 1–817 amino tezacaftor residues was crystallized in the presence of tartrate, ATP and magnesium ions [12].
    Enzymatic properties
    Regulation of ACLY expression and activity ACLY expression is mainly regulated by the transcription factor SREBP-1 (sterol regulatory element binding protein-1) [18]. SREBP-1 up-regulates ACLY at mRNA level via Akt signaling [19]. However, ACLY protein levels are independent of SREBP-1 [20]. It has been suggested that PI3K/Akt pathway stimulates ACLY activity predominantly through phosphorylation of ACLY rather than transcriptional up-regulation. The phosphorylation of ACLY contributes to its protein stabilization [20]. Thr446, Ser450 and Ser454 residues of ACLY are shown to be phosphorylated in vitro[21]. It has also been shown that treatment with PI3K inhibitors does not have a dramatic effect on dephosphorylation and inactivation of ACLY in lung cancer cells. Therefore, it has been suggested that ACLY activity is also regulated by some other pathways [20]. ACLY is reported to be phosphorylated at different sites by other kinases such as nucleoside diphosphate kinase [22] and cyclic AMP dependent protein kinase [23]. Phosphorylation of ACLY is enhanced by glucagon, insulin, vasopressin and transforming growth factor β1 [4].
    Pathways served by ACLY ACLY is a cross-link between glucose metabolism and fatty acid synthesis/mevalonate pathways (Fig. 1). In cytoplasm, glucose-derived citrate is transformed into acetyl-CoA by ACLY. Acetyl CoA is an essential substrate for mevalonate and FA synthesis pathways [14]. In the fatty acid synthesis pathway, acetyl-CoA is carboxylated into malonyl-CoA by acetyl-CoA carboxylase (ACACA). Next, the main lipogenic enzyme fatty-acid-synthase (FASN) performs condensation of acetyl-CoA and malonyl-CoA to produce the long-chain fatty acid palmitate [24]. Acetyl CoA is also a precursor for the mevalonate pathway. This pathway leads to the synthesis of farnesyl-pyrophosphate (FPP). FPP is involved in cholesterol biosynthesis but can also lead to synthesis of geranylgeranyl-pyrophosphate (GG-PP). Both FPP and GG-PP are respectively involved in farnesylation and geranylgeranylation of a variety of proteins [25]. Moreover, acetyl-CoA is required for acetylation reactions, for instance histone acetylation, that modify proteins having critical roles in regulating global chromatin architecture and gene transcription [7]. Recently, it was reported that in the tumor cells with defective mitochondria or in proliferating cells under hypoxic conditions, reductive carboxylation of glutamine-derived α-Ketoglutarate (α-KG) is responsible for supplying citrate for de novo lipogenesis [26], [27].
    Physiological roles associated with ACLY Alterations in expression or activity of ACLY have been observed in different pathological conditions (Fig. 2). Moreover, variations in expression patterns of ACLY have been noticed during different stages of embryonic development. In this section we will describe the physiological roles associated with ACLY in light of these observations.
    Introduction ATP-citrate lyase (ACL, EC 4.1.3.8) catalyzes citrate and CoA to form acetyl-CoA and oxaloacetate accompanied by an ATP hydrolysis. The formation of acetyl-CoA is a key step for lipid biosynthesis [1], [2], [3]. In plants and algae, it was reported that there are three pathways involved in the formation of acetyl-CoA [4], [5] (Fig. 1): acetyl-CoA synthetase (ACS), pyruvate dehydrogenase (PDH), and ACL. It was suggested that the role of ACL is to sustain the cellular flux of the acetyl-CoA to produce lipids in seeds [3]. The study of ACL molecular biology had long been delayed due to its instability, and until 1990 the first animal ACL was cloned [6]. Subsequently, several plant ACLs were reported and the molecular characterization, heterologous expression and activity in Arabidopsis and lupin were described [2], [7]. And it was reported that in Brassica napus ACL was mainly localized in chloroplasts and the relationship between ACL activity and the rate of lipid synthesis was discussed [3].