2yi1: Difference between revisions

Revision as of 15:51, 22 July 2020

Crystal structure of N-Acetylmannosamine kinase in complex with N- acetyl mannosamine 6-phosphate and ADP.Crystal structure of N-Acetylmannosamine kinase in complex with N- acetyl mannosamine 6-phosphate and ADP.

Structural highlights

2yi1 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , , , , , ,
Related:	2yhy, 2yhw
Activity:	N-acylmannosamine kinase, with EC number 2.7.1.60
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Sialic acids are essential components of membrane glycoconjugates. They are responsible for the interaction, structure, and functionality of all deuterostome cells and have major functions in cellular processes in health and diseases. The key enzyme of the biosynthesis of sialic acid is the bifunctional UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase that transforms UDP-N-acetylglucosamine to N-acetylmannosamine (ManNAc) followed by its phosphorylation to ManNAc 6-phosphate and has a direct impact on the sialylation of cell surface components. Here, we present the crystal structures of the human N-acetylmannosamine kinase (MNK) domain of UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase in complexes with ManNAc at 1.64 A resolution, MNK.ManNAc.ADP (1.82 A) and MNK.ManNAc 6-phosphate.ADP (2.10 A). Our findings offer detailed insights in the active center of MNK and serve as a structural basis to design inhibitors. We synthesized a novel inhibitor, 6-O-acetyl-ManNAc, which is more potent than those previously tested. Specific inhibitors of sialic acid biosynthesis may serve to further study biological functions of sialic acid.

Crystal structures of N-acetylmannosamine kinase provide insights into enzyme activity and inhibition.,Martinez J, Nguyen LD, Hinderlich S, Zimmer R, Tauberger E, Reutter W, Saenger W, Fan H, Moniot S J Biol Chem. 2012 Apr 20;287(17):13656-65. Epub 2012 Feb 16. PMID:22343627^[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
↑ Martinez J, Nguyen LD, Hinderlich S, Zimmer R, Tauberger E, Reutter W, Saenger W, Fan H, Moniot S. Crystal structures of N-acetylmannosamine kinase provide insights into enzyme activity and inhibition. J Biol Chem. 2012 Apr 20;287(17):13656-65. Epub 2012 Feb 16. PMID:22343627 doi:10.1074/jbc.M111.318170

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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

[2] 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

[3] 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

[4] 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

[5] 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

[6] 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

[7] 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

[8] 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

[9] 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

[10] 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

[11] 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

[12] 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

[13] 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

[14] 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

[15] 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

[16] 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

[17] 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

[18] Martinez J, Nguyen LD, Hinderlich S, Zimmer R, Tauberger E, Reutter W, Saenger W, Fan H, Moniot S. Crystal structures of N-acetylmannosamine kinase provide insights into enzyme activity and inhibition. J Biol Chem. 2012 Apr 20;287(17):13656-65. Epub 2012 Feb 16. PMID:22343627 doi:10.1074/jbc.M111.318170

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

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[12]

[13]

[14]

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[17]

[18]

@@ Line 1: / Line 1: @@
 ==Crystal structure of N-Acetylmannosamine kinase in complex with N- acetyl mannosamine 6-phosphate and ADP.==
-<StructureSection load='2yi1' size='340' side='right' caption='[[2yi1]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
+<StructureSection load='2yi1' size='340' side='right'caption='[[2yi1]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2yi1]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YI1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2YI1 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2yi1]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YI1 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2YI1 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2PE:NONAETHYLENE+GLYCOL'>2PE</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=BM3:2-(ACETYLAMINO)-2-DEOXY-ALPHA-D-MANNOPYRANOSE'>BM3</scene>, <scene name='pdbligand=BMX:2-(ACETYLAMINO)-2-DEOXY-6-O-PHOSPHONO-ALPHA-D-MANNOPYRANOSE'>BMX</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2PE:NONAETHYLENE+GLYCOL'>2PE</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=BM3:2-(ACETYLAMINO)-2-DEOXY-ALPHA-D-MANNOPYRANOSE'>BM3</scene>, <scene name='pdbligand=BMX:2-(ACETYLAMINO)-2-DEOXY-6-O-PHOSPHONO-ALPHA-D-MANNOPYRANOSE'>BMX</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2yhy|2yhy]], [[2yhw|2yhw]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/N-acylmannosamine_kinase N-acylmannosamine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.60 2.7.1.60] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2yi1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yi1 OCA], [http://pdbe.org/2yi1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2yi1 RCSB], [http://www.ebi.ac.uk/pdbsum/2yi1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2yi1 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2yi1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yi1 OCA], [http://pdbe.org/2yi1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2yi1 RCSB], [http://www.ebi.ac.uk/pdbsum/2yi1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2yi1 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 27: / Line 27: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: N-acylmannosamine kinase]]
 [[Category: Fan, H]]

2yi1: Difference between revisions

Revision as of 15:51, 22 July 2020

Crystal structure of N-Acetylmannosamine kinase in complex with N- acetyl mannosamine 6-phosphate and ADP.Crystal structure of N-Acetylmannosamine kinase in complex with N- acetyl mannosamine 6-phosphate and ADP.

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

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2yi1: Difference between revisions

Revision as of 15:51, 22 July 2020

Crystal structure of N-Acetylmannosamine kinase in complex with N- acetyl mannosamine 6-phosphate and ADP.Crystal structure of N-Acetylmannosamine kinase in complex with N- acetyl mannosamine 6-phosphate and ADP.

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

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