| Structural highlights
Disease
[GLCNE_HUMAN] Defects in GNE are a cause of sialuria (SIALURIA) [MIM:269921]; also known as sialuria French type. In sialuria, free sialic acid accumulates in the cytoplasm and gram quantities of neuraminic acid are secreted in the urine. The metabolic defect involves lack of feedback inhibition of UDP-GlcNAc 2-epimerase by CMP-Neu5Ac, resulting in constitutive overproduction of free Neu5Ac. Clinical features include variable degrees of developmental delay, coarse facial features and hepatomegaly. Sialuria inheritance is autosomal dominant.[1] [2] [3] [4] Defects in GNE are the cause of inclusion body myopathy type 2 (IBM2) [MIM:600737]. Hereditary inclusion body myopathies are a group of neuromuscular disorders characterized by adult onset, slowly progressive distal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. IBM2 is an autosomal recessive disorder affecting mainly leg muscles, but with an unusual distribution that spares the quadriceps as also observed in Nonaka myopathy.[5] [6] [7] [8] [9] [10] [11] Defects in GNE are the cause of Nonaka myopathy (NM) [MIM:605820]; also known as distal myopathy with rimmed vacuoles (DMRV). NM is an autosomal recessive muscular disorder, allelic to inclusion body myopathy 2. It is characterized by weakness of the anterior compartment of the lower limbs with onset in early adulthood, and sparing of the quadriceps muscles. As the inclusion body myopathy, NM is histologically characterized by the presence of numerous rimmed vacuoles without inflammatory changes in muscle specimens.[12] [13] [14] [15] [16]
Function
[GLCNE_HUMAN] Regulates and initiates biosynthesis of N-acetylneuraminic acid (NeuAc), a precursor of sialic acids. Plays an essential role in early development (By similarity). Required for normal sialylation in hematopoietic cells. Sialylation is implicated in cell adhesion, signal transduction, tumorigenicity and metastatic behavior of malignant cells.[17]
Publication Abstract from PubMed
The bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) plays a key role in sialic acid production. It is different from the non-hydrolyzing enzymes for bacterial cell wall biosynthesis, and it is feed-back inhibited by the downstream product CMP-Neu5Ac. Here the complex crystal structure of the N-terminal epimerase part of human GNE shows a tetramer in which UDP binds to the active site and CMP-Neu5Ac binds to the dimer-dimer interface. The enzyme is locked in a tightly closed conformation. By comparing the UDP-binding modes of the non-hydrolyzing and hydrolyzing UDP-GlcNAc epimerases, we propose a possible explanation for the mechanistic difference. While the epimerization reactions of both enzymes are similar, Arg113 and Ser302 of GNE are likely involved in product hydrolysis. On the other hand, the CMP-Neu5Ac binding mode clearly elucidates why mutations in Arg263 and Arg266 can cause sialuria. Moreover, full-length modelling suggests a channel for ManNAc trafficking within the bifunctional enzyme.
Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis.,Chen SC, Huang CH, Lai SJ, Yang CS, Hsiao TH, Lin CH, Fu PK, Ko TP, Chen Y Sci Rep. 2016 Mar 16;6:23274. doi: 10.1038/srep23274. PMID:26980148[18]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Weiss P, Tietze F, Gahl WA, Seppala R, Ashwell G. Identification of the metabolic defect in sialuria. J Biol Chem. 1989 Oct 25;264(30):17635-6. PMID:2808337
- ↑ Seppala R, Lehto VP, Gahl WA. Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme. Am J Hum Genet. 1999 Jun;64(6):1563-9. PMID:10330343 doi:S0002-9297(07)63658-1
- ↑ Ferreira H, Seppala R, Pinto R, Huizing M, Martins E, Braga AC, Gomes L, Krasnewich DM, Sa Miranda MC, Gahl WA. Sialuria in a Portuguese girl: clinical, biochemical, and molecular characteristics. Mol Genet Metab. 1999 Jun;67(2):131-7. PMID:10356312 doi:10.1006/mgme.1999.2852
- ↑ Leroy JG, Seppala R, Huizing M, Dacremont G, De Simpel H, Van Coster RN, Orvisky E, Krasnewich DM, Gahl WA. Dominant inheritance of sialuria, an inborn error of feedback inhibition. Am J Hum Genet. 2001 Jun;68(6):1419-27. Epub 2001 Apr 18. PMID:11326336 doi:10.1086/320598
- ↑ Eisenberg I, Avidan N, Potikha T, Hochner H, Chen M, Olender T, Barash M, Shemesh M, Sadeh M, Grabov-Nardini G, Shmilevich I, Friedmann A, Karpati G, Bradley WG, Baumbach L, Lancet D, Asher EB, Beckmann JS, Argov Z, Mitrani-Rosenbaum S. The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet. 2001 Sep;29(1):83-7. PMID:11528398 doi:10.1038/ng718
- ↑ Darvish D, Vahedifar P, Huo Y. Four novel mutations associated with autosomal recessive inclusion body myopathy (MIM: 600737). Mol Genet Metab. 2002 Nov;77(3):252-6. PMID:12409274
- ↑ Vasconcelos OM, Raju R, Dalakas MC. GNE mutations in an American family with quadriceps-sparing IBM and lack of mutations in s-IBM. Neurology. 2002 Dec 10;59(11):1776-9. PMID:12473769
- ↑ Broccolini A, Pescatori M, D'Amico A, Sabino A, Silvestri G, Ricci E, Servidei S, Tonali PA, Mirabella M. An Italian family with autosomal recessive inclusion-body myopathy and mutations in the GNE gene. Neurology. 2002 Dec 10;59(11):1808-9. PMID:12473780
- ↑ Eisenberg I, Grabov-Nardini G, Hochner H, Korner M, Sadeh M, Bertorini T, Bushby K, Castellan C, Felice K, Mendell J, Merlini L, Shilling C, Wirguin I, Argov Z, Mitrani-Rosenbaum S. Mutations spectrum of GNE in hereditary inclusion body myopathy sparing the quadriceps. Hum Mutat. 2003 Jan;21(1):99. PMID:12497639 doi:10.1002/humu.9100
- ↑ Del Bo R, Baron P, Prelle A, Serafini M, Moggio M, Fonzo AD, Castagni M, Bresolin N, Comi GP. Novel missense mutation and large deletion of GNE gene in autosomal-recessive inclusion-body myopathy. Muscle Nerve. 2003 Jul;28(1):113-7. PMID:12811782 doi:10.1002/mus.10391
- ↑ Broccolini A, Ricci E, Cassandrini D, Gliubizzi C, Bruno C, Tonoli E, Silvestri G, Pescatori M, Rodolico C, Sinicropi S, Servidei S, Zara F, Minetti C, Tonali PA, Mirabella M. Novel GNE mutations in Italian families with autosomal recessive hereditary inclusion-body myopathy. Hum Mutat. 2004 Jun;23(6):632. PMID:15146476 doi:10.1002/humu.9252
- ↑ Arai A, Tanaka K, Ikeuchi T, Igarashi S, Kobayashi H, Asaka T, Date H, Saito M, Tanaka H, Kawasaki S, Uyama E, Mizusawa H, Fukuhara N, Tsuji S. A novel mutation in the GNE gene and a linkage disequilibrium in Japanese pedigrees. Ann Neurol. 2002 Oct;52(4):516-9. PMID:12325084 doi:10.1002/ana.10341
- ↑ Kayashima T, Matsuo H, Satoh A, Ohta T, Yoshiura K, Matsumoto N, Nakane Y, Niikawa N, Kishino T. Nonaka myopathy is caused by mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE). J Hum Genet. 2002;47(2):77-9. PMID:11916006 doi:10.1007/s100380200004
- ↑ Tomimitsu H, Ishikawa K, Shimizu J, Ohkoshi N, Kanazawa I, Mizusawa H. Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene. Neurology. 2002 Aug 13;59(3):451-4. PMID:12177386
- ↑ Nishino I, Noguchi S, Murayama K, Driss A, Sugie K, Oya Y, Nagata T, Chida K, Takahashi T, Takusa Y, Ohi T, Nishimiya J, Sunohara N, Ciafaloni E, Kawai M, Aoki M, Nonaka I. Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology. 2002 Dec 10;59(11):1689-93. PMID:12473753
- ↑ Yabe I, Higashi T, Kikuchi S, Sasaki H, Fukazawa T, Yoshida K, Tashiro K. GNE mutations causing distal myopathy with rimmed vacuoles with inflammation. Neurology. 2003 Aug 12;61(3):384-6. PMID:12913203
- ↑ Keppler OT, Hinderlich S, Langner J, Schwartz-Albiez R, Reutter W, Pawlita M. UDP-GlcNAc 2-epimerase: a regulator of cell surface sialylation. Science. 1999 May 21;284(5418):1372-6. PMID:10334995
- ↑ Chen SC, Huang CH, Lai SJ, Yang CS, Hsiao TH, Lin CH, Fu PK, Ko TP, Chen Y. Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis. Sci Rep. 2016 Mar 16;6:23274. doi: 10.1038/srep23274. PMID:26980148 doi:https://dx.doi.org/10.1038/srep23274
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