Regulation and pathophysiological implications of UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) as the key enzyme of sialic acid biosynthesis

2009 ◽  
Vol 390 (7) ◽  
Author(s):  
Stefan O. Reinke ◽  
Gerhard Lehmer ◽  
Stephan Hinderlich ◽  
Werner Reutter
Keyword(s):  
Sialic Acid ◽  
Crucial Role ◽  
Feedback Inhibition ◽  
Acid Biosynthesis ◽  
Knock Out ◽  
Acetylneuraminic Acid ◽  
Kinase C ◽  
Key Enzyme ◽  
Hereditary Inclusion Body Myopathy

AbstractThe key enzyme for the biosynthesis ofN-acetylneuraminic acid, from which all other sialic acids are formed, is the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). GNE is a highly conserved protein found throughout the animal kingdom. Its highest expression is seen in the liver and placenta. GNE is regulated by a variety of biochemical means, including tetramerization promoted by the substrate UDP-GlcNAc, phosphorylation by protein kinase C and feedback inhibition by CMP-Neu5Ac, which is defect in the human disease sialuria. GNE knock-out in mice leads to embryonic lethality, emphasizing the crucial role of this key enzyme for sialic acid biosynthesis. The metabolic capacity to synthesize sialic acid and CMP-sialic acid upon ManNAc loads is amazingly high. An additional characteristic of GNE is its interaction with proteins involved in the regulation of development, which might play a crucial role in the hereditary inclusion body myopathy. Due to the importance of increased concentrations of tumor-surface sialic acid, first attempts to find inhibitors of GNE have been successful.

scholarly journals Regulation of N-glycolylneuraminic acid biosynthesis in developing pig small intestine

2003 ◽  
Vol 370 (2) ◽  
pp. 601-607 ◽  
Author(s):  
Yanina N. MALYKH ◽  
Timothy P. KING ◽  
Elizabeth LOGAN ◽  
Denise KELLY ◽  
Roland SCHAUER ◽  
...  
Keyword(s):  
Small Intestine ◽  
Sialic Acid ◽  
Post Partum ◽  
Acid Biosynthesis ◽  
Acetylneuraminic Acid ◽  
Total Sialic Acid ◽  
Key Factor ◽  
Developmental Phases ◽  
Cytosolic Factors

N-Glycolylneuraminic acid (Neu5Gc), an abundant sialic acid in animal glycoconjugates, is formed by the enzyme CMP-N-acetylneuraminic acid (CMP-Neu5Ac) hydroxylase. The amount of Neu5Gc relative to other sialic acids is highly dependent on the species, tissue and developmental stage. Although the activity of the hydroxylase is a key factor in controlling Neu5Gc incorporation in adult animals, little is known about the regulation of hydroxylase expression and the role of this enzyme in determining changes in Neu5Gc during development. Using pig small intestine as a model system, the appearance of total sialic acid and the regulation of Neu5Gc biosynthesis during development were studied in various regions of this tissue. The amount of total sialic acid and Neu5Gc declined markedly in 2 weeks after birth. Although in subsequent developmental phases there were no positional differences in total sialic acid, a significant proximal-to-distal increase in Neu5Gc was detected. In all cases, a good correlation between the amount of Neu5Gc, the activity of the hydroxylase and the level of hydroxylase mRNA was observed. However, Western-blot analysis revealed considerable accumulation of less active enzyme in the post partum period, which persisted until adulthood. No evidence for cytosolic factors influencing the hydroxylase activity or for the formation of truncated enzyme was found, raising the possibility that other regulatory mechanisms are involved. The relevance of these results in the formation of Neu5Gc as a receptor for certain pig enteric pathogens is also discussed.

scholarly journals Functional Specificities of Brm and Brg-1 Swi/Snf ATPases in the Feedback Regulation of Hepatic Bile Acid Biosynthesis

2009 ◽  
Vol 29 (23) ◽  
pp. 6170-6181 ◽  
Author(s):  
Ji Miao ◽  
Sungsoon Fang ◽  
Jiyoung Lee ◽  
Clay Comstock ◽  
Karen E. Knudsen ◽  
...  
Keyword(s):  
Bile Acid ◽  
Feedback Inhibition ◽  
Feedback Regulation ◽  
Farnesoid X Receptor ◽  
Bile Acid Metabolism ◽  
Acid Biosynthesis ◽  
Bile Acid Biosynthesis ◽  
Key Enzyme ◽  
Accessible Chromatin

ABSTRACT Bile acid homeostasis is critical in maintaining health and is primarily regulated by the nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP). Bile acid-activated FXR indirectly inhibits expression of cholesterol 7α hydroxylase (CYP7A1), a key enzyme in conversion of cholesterol to bile acids, by induction of SHP. We recently demonstrated that SHP inhibits CYP7A1 transcription by recruiting chromatin-modifying cofactors, including Brm-Swi/Snf. Swi/Snf complexes contain either Brm or Brg-1 ATPases, and whether these subunits have distinct functions remains unclear. We have examined the role of these subunits in regulation of bile acid metabolism under physiological conditions by FXR and SHP. Brg-1 interacted with FXR and enhanced FXR-mediated transactivation of SHP, whereas Brm interacted with SHP and enhanced SHP-mediated repression of CYP7A1 and, interestingly, auto-repression of SHP. Chromatin immunoprecipitation and remodeling studies revealed that after treatment with FXR agonists, Brg-1 was recruited to the SHP promoter, resulting in transcriptionally active accessible chromatin, whereas Brm was recruited to both CYP7A1 and SHP promoters, resulting in inactive inaccessible chromatin. Our studies demonstrate that Brm and Brg-1 have distinct functions in the regulation of two key genes, CYP7A1 and SHP, within a single physiological pathway, feedback inhibition of bile acid biosynthesis, by differentially targeting SHP and FXR.

scholarly journals Characterization of Ligand Binding to the Bifunctional Key Enzyme in the Sialic Acid Biosynthesis by NMR

2004 ◽  
Vol 279 (53) ◽  
pp. 55722-55727 ◽  
Author(s):  
Andrew J. Benie ◽  
Astrid Blume ◽  
Richard R. Schmidt ◽  
Werner Reutter ◽  
Stephan Hinderlich ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Ligand Binding ◽  
Acid Biosynthesis ◽  
Key Enzyme

scholarly journals Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Sheng-Chia Chen ◽  
Chi-Hung Huang ◽  
Shu-Jung Lai ◽  
Chia Shin Yang ◽  
Tzu-Hung Hsiao ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Acid Biosynthesis ◽  
Key Enzyme

scholarly journals Inhibition of the key enzyme of sialic acid biosynthesis by C6-Se modified N-acetylmannosamine analogs

2016 ◽  
Vol 7 (6) ◽  
pp. 3928-3933 ◽  
Author(s):  
Olaia Nieto-Garcia ◽  
Paul R. Wratil ◽  
Long D. Nguyen ◽  
Verena Böhrsch ◽  
Stephan Hinderlich ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Acid Biosynthesis ◽  
Key Enzyme ◽  
Potential Inhibitors

Synthetically accessible C6-analogs ofN-acetylmannosamine (ManNAc) were tested as potential inhibitors of the bifunctional UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE/MNK), the key enzyme of sialic acid biosynthesis.

scholarly journals Regulation of colominic acid biosynthesis by temperature: Role of cytidine 5′-monophosphateN-acetylneuraminic acid synthetase

FEBS Letters ◽  
1989 ◽  
Vol 250 (2) ◽  
pp. 429-432 ◽  
Author(s):  
Camino González-Clemente ◽  
José M. Luengo ◽  
Leandro B. Rodríguez-Aparicio ◽  
Angel Reglero
Keyword(s):  
Acid Biosynthesis ◽  
Acetylneuraminic Acid ◽  
Colominic Acid

scholarly journals Sialic Acid Species as a Determinant of the Host Range of Influenza A Viruses

2000 ◽  
Vol 74 (24) ◽  
pp. 11825-11831 ◽  
Author(s):  
Yasuo Suzuki ◽  
Toshihiro Ito ◽  
Takashi Suzuki ◽  
Robert E. Holland ◽  
Thomas M. Chambers ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Viral Replication ◽  
Influenza A ◽  
Lectin Binding ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Acetylneuraminic Acid ◽  
Human Viruses ◽  
Immunohistochemical Analyses

ABSTRACT The distribution of sialic acid (SA) species varies among animal species, but the biological role of this variation is largely unknown. Influenza viruses differ in their ability to recognize SA-galactose (Gal) linkages, depending on the animal hosts from which they are isolated. For example, human viruses preferentially recognize SA linked to Gal by the α2,6(SAα2,6Gal) linkage, while equine viruses favor SAα2,3Gal. However, whether a difference in relative abundance of specific SA species (N-acetylneuraminic acid [NeuAc] andN-glycolylneuraminic acid [NeuGc]) among different animals affects the replicative potential of influenza viruses is uncertain. We therefore examined the requirement for the hemagglutinin (HA) for support of viral replication in horses, using viruses whose HAs differ in receptor specificity. A virus with an HA recognizing NeuAcα2,6Gal but not NeuAcα2,3Gal or NeuGcα2,3Gal failed to replicate in horses, while one with an HA recognizing the NeuGcα2,3Gal moiety replicated in horses. Furthermore, biochemical and immunohistochemical analyses and a lectin-binding assay demonstrated the abundance of the NeuGcα2,3Gal moiety in epithelial cells of horse trachea, indicating that recognition of this moiety is critical for viral replication in horses. Thus, these results provide evidence of a biological effect of different SA species in different animals.

scholarly journals Domain-specific characteristics of the bifunctional key enzyme of sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase

2004 ◽  
Vol 384 (3) ◽  
pp. 599-607 ◽  
Author(s):  
Astrid BLUME ◽  
Wenke WEIDEMANN ◽  
Ulrich STELZL ◽  
Erich E. WANKER ◽  
Lothar LUCKA ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Kinase Domain ◽  
Complete Loss ◽  
Bifunctional Enzyme ◽  
Acid Biosynthesis ◽  
Domain Specific ◽  
Cell Matrix ◽  
C Terminus ◽  
Key Enzyme ◽  
Cell Matrix Interactions

UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase is a bifunctional enzyme, which initiates and regulates sialic acid biosynthesis. Sialic acids are important compounds of mammalian glycoconjugates, mediating several biological processes, such as cell–cell or cell–matrix interactions. In order to characterize the function of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, a number of deletion mutants were generated, lacking either parts of the N-terminal epimerase or the C-terminal kinase domain. N-terminal deletion of only 39 amino acids results in a complete loss of epimerase activity. Deletions in the C-terminal part result in a reduction or complete loss of kinase activity, depending on the size of the deletion. Deletions at either the N- or the C-terminus also result in a reduction of the other enzyme activity. These results indicate that a separate expression of both domains is possible, but that a strong intramolecular dependency of the two domains has arisen during evolution of the enzyme. N-terminal, as well as C-terminal, mutants tend to form trimers, in addition to the hexameric structure of the native enzyme. These results and yeast two-hybrid experiments show that structures required for dimerization are localized within the kinase domain, and a potential trimerization site is possibly located in a region between the two domains. In conclusion, our results reveal that the activities, as well as the oligomeric structure, of this bifunctional enzyme seem to be organized and regulated in a complex manner.

scholarly journals The solute carrier SLC16A12 is critical for creatine and guanidinoacetate handling in the kidney

2021 ◽  
Author(s):  
Sophia N Verouti ◽  
Delphine Lambert ◽  
Déborah Mathis ◽  
Ganesh Pathare ◽  
Geneviève Escher ◽  
...  
Keyword(s):  
Feedback Inhibition ◽  
Basolateral Membrane ◽  
Dominant Negative ◽  
Renal Physiology ◽  
Heterozygous Mutation ◽  
Lower Plasma ◽  
Knock Out ◽  
Proximal Tubular ◽  
Rate Limiting

A heterozygous mutation (c.643C.A; p.Q215X) in the creatine transporter SLC16A12 was proposed to cause a syndrome with juvenile cataracts, microcornea and glucosuria in humans. To further explore the role of SLC16A12 in renal physiology and decipher the mechanism underlying the phenotype of humans with the SLC16A12 mutation, we studied Slc16a12 knock-out (KO) rats. Slc16a12 KO rats had lower plasma levels and increased absolute and fractional urinary excretion of creatine and its precursor guanidinoacetate (GAA). Slc16a12 KO rats displayed lower plasma and urinary creatinine levels, but GFR was normal. The phenotype of heterozygous rats was indistinguishable from wild-type (WT) rats. Renal artery to vein (RAV) concentration differences in WT rats were negative for GAA and positive for creatinine. However, RAV differences for GAA were similar in Slc16a12 KO rats, indicating incomplete compensation of urinary GAA losses by renal GAA synthesis. Together, our results reveal that Slc16a12 in the basolateral membrane of the proximal tubule is critical for reabsorption of creatine and GAA. Our data suggest a dominant-negative mechanism underlying the phenotype of humans affected by the heterozygous SLC16A12 mutation. Furthermore, in the absence of Slc16a12, urinary losses of GAA are not adequately compensated by increased tubular synthesis, caused by feedback inhibition of the rate limiting enzyme L-arginine:glycine amidinotransferase by creatine in proximal tubular cells.

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