Hindawi BioMed Research International Volume 2020, Article ID 7091718, 7 pages https://doi.org/10.1155/2020/7091718 Review Article Uridine Metabolism and Its Role in Glucose, Lipid, and Amino Acid Homeostasis Yumei Zhang, Songge Guo, Chunyan Xie , and Jun Fang College of Bioscience and Biotechnology, College of Resources and Environment, Hunan Agricultural University, Changsha, 410128 Hunan, China Correspondence should be addressed to Chunyan Xie; [email protected] and Jun Fang; [email protected] Received 10 December 2019; Accepted 4 February 2020; Published 15 April 2020 Academic Editor: Flavia Prodam Copyright © 2020 Yumei Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Pyrimidine nucleoside uridine plays a critical role in maintaining cellular function and energy metabolism. In addition to its role in nucleoside synthesis, uridine and its derivatives contribute to reduction of cytotoxicity and suppression of drug-induced hepatic steatosis. Uridine is mostly present in blood and cerebrospinal fluid, where it contributes to the maintenance of basic cellular functions affected by UPase enzyme activity, feeding habits, and ATP depletion. Uridine metabolism depends on three stages: de novo synthesis, salvage synthesis pathway and catabolism, and homeostasis, which is tightly relating to glucose homeostasis and lipid and amino acid metabolism. This review is devoted to uridine metabolism and its role in glucose, lipid, and amino acid homeostasis. 1. Introduction In contrast, uridine can also regulate systemic homeosta- sis by regulating enzymes and their reaction products. Uridine, a necessary pyrimidine nucleotide for RNA synthesis, Uridine is thought to regulate the mitochondrial respiratory can be synthesized de novo in mammals [1–3]. Uridine has chain via the dihydroorotate dehydrogenase (DHODH) been widely used in reducing cytotoxicity [4] and improving enzyme, and since mitochondrial dysfunction is involved in neurophysiological functions [5, 6]. In addition, short-term many human diseases, uridine could be used as a therapeutic uridine coadministration with tamoxifen could suppress drug for mitochondrial diseases [10]. Furthermore, the accu- hepatic steatosis [2, 7–10]. In humans, uridine is present in mulation of orotate, an intermediate product in the process the blood and cerebrospinal fluid, and the content of uridine of uridine de novo synthesis, induces intracellular lipid accu- in plasma is much higher than that in other purine and mulation [14]. Accordingly, in this review, we focus on the pyrimidine nucleosides [7, 11]. Due to their inability to factors that influence uridine concentration and the role of synthesize uridine, most tissues utilize plasma uridine to uridine in the metabolism of glucose, lipid, and amino acid. maintain basic cellular functions [1, 12]. Thus, plasma uridine may be used for the synthesis of endogenous pyrim- 2. Uridine Biosynthesis and idine. The biosynthesis of uridine is regulated by the liver and Catabolism Pathway adipose tissues, and the excretion of uridine is mainly achieved via the kidneys or by pyrimidine catabolism in It is acknowledged that pyrimidine nucleotide metabolism tissues [13]. Many research studies have demonstrated that involves three pathways: de novo synthesis, salvage synthesis uridine homeostasis is affected by a variety of factors to reg- pathway, and catabolism. Within the cell, nucleotides can be ulate systemic metabolism. Factors recognized for regulating synthesized from a simple metabolite by the de novo synthe- the concentration of uridine include uridine phosphorylase sis pathway or recycled by the salvage synthesis pathway [1]. (UPase), feeding behavior, and ATP depletion. When endogenous supply is insufficient to maintain normal 2 BioMed Research International body functions, uridine is mainly exogenously supplemented phosphorylase (UPase) encoded by the UPP gene by diet to maintain normal growth and cell function [15]. (EC=2.4.2.3). UPase has two homologous forms in verte- During its catabolism, uridine is converted to β-alanine and brates: UPase1 and UPase2 [10, 11, 23]. UPase1, encoded followed by secretion to the brain and muscle tissues [1]. by the UPP1 gene, regulates uridine homeostasis and is ubiquitously expressed. Inhibition of the enzymatic activity 2.1. Uridine Biosynthesis. Uridine de novo synthesis originates of UPase1 or UPase1 gene knockout results in elevated levels from glutamine and is catalyzed by the CAD protein (which of uridine in plasma and tissues [11, 24]. UPase2 is a liver- fi encodes the rate-limiting enzymes during uridine biosynthe- speci c protein encoded by the UPP2 gene and is indispens- sis). CAD is a multidomain enzyme comprised of carbamoyl able for pyrimidine salvage reactions [2, 11]. Inhibition of phosphate synthetase (CPS II, EC=6.3.5.5), aspartic transcar- the enzymatic activity of UPase2 increases the level of bamoylase (ATCase, EC=2.1.3.2), and dihydroorotase (DHO, endogenous uridine in the liver, thereby protecting the liver EC=3.5.2.3), in which CPS II is the rate-limiting enzyme, and against drug-induced lipid accumulation [2, 25]. Next, ′ uracil is further decomposed into dihydrouracil and N-car- regulation of CPS II is mediated by uridine 5 -triphosphate β (UTP) feedback inhibition and phosphoribosyl pyrophos- bamoyl- -alanine by dihydropyrimidine dehydrogenase phate (PRPP) activation [15]. In the de novo pathway, CAD (DPD) and hydropyrimidine hydratase (also known as dihy- dropyrimidinase), which is further converted to β-alanine by catalyzed glutamine produces the intermediate metabolites β β carbamoyl phosphate, carbamoyl aspartate, and dihydrooro- -ureidopropionase (EC=3.5.1.6) [1, 10]. -Alanine is tate (Figure 1). excreted or enters other tissues, such as the brain and muscle. The fourth step in pyrimidine biosynthesis is catalyzed by DHODH, to form an important intermediate, orotate. The accumulation of orotate may induce intracellular lipid 3. The Regulation Mechanism of the accumulation [10]. DHODH is a mitochondrial, respiratory Uridine Concentration chain-coupled enzyme on the outer surface of the mitochon- drial inner membrane, which links pyrimidine biosynthesis The plasma uridine concentration in mammals is between 3 to mitochondrial energy metabolism [10, 15]. Then, orotate and 8 μM, which is higher than other pyrimidine nucleotides is converted to orotidine monophosphate (OMP) and and bases [1, 26]. Most tissues cannot synthesize uridine; uridine monophosphate (UMP) by orotate phosphoribosyl- thus, use plasma as a uridine source [7, 11]. Plasma uridine transferase and orotidine 5′-phosphate decarboxylase, concentration is tightly controlled by a variety of factors in respectively. Then, UMP is dephosphorylated to uridine by both humans and rodents [1, 27]. However, there is no nucleotidase or formed from cytidine by cytidine deaminase review of factors that regulate the concentration of uridine (EC=3.5.4.5) [1, 10, 12]. at present. Therefore, we next focus on factors that regulate A recent study has shown that resting/low proliferating the concentration of uridine and its mechanisms. cells rely mainly on the nucleotide salvage pathway to synthe- size RNA [16]. Also, uridine can be obtained from UTP and ′ 3.1. Feeding Behavior Regulates the Plasma Concentration of cytosine 5 -triphosphate (CTP) via the pyrimidine salvage Uridine. A series of recent studies indicate that the dynamic pathway. UTP is also involved in glycogen synthesis, protein regulation of plasma uridine is related to feeding behavior glycosylation, and membrane phospholipid biosynthesis [11, 23]. As the main organ in uridine biosynthesis, the liver – [17 19]. In the pyrimidine nucleotide salvage synthesis path- maintains uridine homeostasis by regulating glucose metabo- way, uridine-cytidine kinase 2 (UCK2) acts as a phosphory- lism during different feeding states [12, 27]. In the fed period, lase responsible for phosphorylating pyrimidine nucleotides uridine synthesis occurs mainly in the liver tissue. However, in (uridine and cytidine) to the corresponding monophosphates the fasted period, uridine synthesis depends on adipocytes, as [15]. Nucleoside monophosphate kinase further phosphory- the liver focuses on glucose production [12]. Experiments to ′ lates UMP and CMP to produce uridine 5 -diphosphate study how fasting and refeeding can cause changes in plasma (UDP) and cytosine 5′-diphosphate (CDP). UDP and CDP uridine levels were performed in C57BL/6 mice, Sprague- are further phosphorylated by the nucleoside diphosphate Dawley rats, and healthy women. In the fasted state, adipose kinase to produce UTP and CTP. Subsequently, UTP and tissue elevated the plasma concentration of uridine via uridine CTP are used only for gene duplication. During nucleic acid biosynthesis, while plasma uridine levels decreased rapidly catabolism, some nucleoside monophosphates (NMPs) are after refeeding [27]. The reduction is caused by a decrease in released and reused in the salvage synthesis pathway by uridine synthesis in adipocytes and an increase in uridine UCK2 [20]. In mammals, UCK2 is allosterically activated by clearance in bile [27–29]. ATP to synthesize the pyrimidine nucleotides required for Uridine can be catalyzed in vivo into uracil by uridine cellular metabolism. Nucleotide production is controlled by phosphorylase. It is hypothesized that