Mannosidase, Alpha, Class 1 (MAN1A1 (Golgi Alpha-Mannnosidase IA), Man1A2 (Golgi Alpha-Mannosidase IB), MAN1B1(ER Alpha-Mannosidase I), MAN1C1 (Golgi Alpha-Mannosidase IC))

  • Kelley W. Moremen
  • Alison V. Nairn
Reference work entry


The maturation of N-glycans is initiated within the lumen of the endoplasmic reticulum (ER) immediately after transfer of the oligosaccharide precursor to nascent polypeptide chains (Kornfeld and Kornfeld 1985). These glycan processing steps include the sequential cleavage of three glucose (Glc) residues and four α1,2-mannose (α1,2-Man) residues prior to the addition of a GlcNAc residue and cleavage of the final α1,3-Man and α1,6-Man residues. The resulting GlcNAcMan3GlcNAc2-Asn core structure is then extended in the Golgi complex into complex type oligosaccharides (Fig. 115.1). The Glc residues are cleaved by a pair of endoplasmic reticulum (ER) resident glucosidases (MOGS and the heterodimeric GANAB/PRKCSH), and the α1,2-Man residues are removed by a family of α1,2-mannosidases that reside in the ER and Golgi complex. The α1,2-mannosidases are comprised of seven related gene products (Mast et al. 2005; Mast and Moremen 2006; Moremen and Molinari 2006). These enzymes are members of CAZy glycosylhydrolase family 47 (GH47) (Coutinho et al. 2003) and can be distinguished from the later acting α1,3-/α1,6-mannosidases in the Golgi complex, lysosomes, and cytosol (GH38 enzymes) by differences in sequence, protein structural domains, enzymatic characteristics, inhibitor profiles, and catalytic mechanisms (Moremen 2000; Moremen and Molinari 2006; Moremen and Touster 1988; Moremen et al. 1994). This chapter is focused on the N-glycan processing enzymes, ER α-mannosidase I (MAN1B1), and three Golgi α1,2-mannosidases (Golgi α-mannosidase IA (MAN1A1), Golgi α-mannosidase IB (MAN1A2), and Golgi α-mannosidase IC (MAN1C1)). Brief mention of the related EDEM proteins (EDEM1, EDEM2, and EDEM3) is made for comparison, as these ER-resident proteins are thought to play roles in targeting of misfolded proteins for ER-associated degradation (ERAD) rather than processing of glycoproteins for maturation to complex type structures within the secretory pathway.


Endoplasmic Reticulum Golgi Complex GH47 Enzyme Active Site Cleft Nascent Polypeptide Chain 
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  1. Atkinson PH, Lee JT (1984) Co-translational excision of a-glucose and α-mannose in nascent vesicular stomatitis virus G protein. J Cell Biol 98:2245–2249PubMedCrossRefGoogle Scholar
  2. Bause E, Breuer W, Schweden J, Roeser R, Geyer R (1992) Effect of substrate structure on the activity of Man9-mannosidase from pig liver involved in N-linked oligosaccharide processing. Eur J Biochem 208:451–457PubMedCrossRefGoogle Scholar
  3. Bause E, Bieberich E, Rolfs A, Volker C, Schmidt B (1993) Molecular cloning and primary structure of Man9-mannosidase from human kidney. Eur J Biochem 217:535–540PubMedCrossRefGoogle Scholar
  4. Bieberich E, Bause E (1995) Man9-mannosidase from human kidney is expressed in COS cells as a Golgi- resident type II transmembrane N-glycoprotein. Eur J Biochem 233:644–649PubMedCrossRefGoogle Scholar
  5. Bieberich E, Treml K, Volker C, Rolfs A, Kalz-Fuller B, Bause E (1997) Man9-mannosidase from pig liver is a type-II membrane protein that resides in the endoplasmic reticulum. cDNA cloning and expression of the enzyme in COS 1 cells. Eur J Biochem 246:681–689PubMedCrossRefGoogle Scholar
  6. Burke J, Lipari F, Igdoura S, Herscovics A (1996) The Saccharomyces cerevisiae processing α1,2-mannosidase is localized in the endoplasmic reticulum, independently of known retrieval motifs. Eur J Cell Biol 70:298–305PubMedGoogle Scholar
  7. Byrd JC, Tarentino AL, Maley F, Atkinson PH, Trimble RB (1982) Glycoprotein synthesis in yeast. Identification of Man8GlcNAc2 as an essential intermediate in oligosaccharide processing. J Biol Chem 257:14657–14666PubMedGoogle Scholar
  8. Camirand A, Heysen A, Grondin B, Herscovics A (1991) Glycoprotein biosynthesis in Saccharomyces cerevisiae. Isolation and characterization of the gene encoding a specific processing α-mannosidase. J Biol Chem 266:15120–15127PubMedGoogle Scholar
  9. Clerc S, Hirsch C, Oggier DM, Deprez P, Jakob C, Sommer T, Aebi M (2009) Htm1 protein generates the N-glycan signal for glycoprotein degradation in the endoplasmic reticulum. J Cell Biol 184:159–172PubMedCrossRefGoogle Scholar
  10. Coutinho PM, Deleury E, Davies GJ, Henrissat B (2003) An evolving hierarchical family classification for glycosyltransferases. J Mol Biol 328:307–317PubMedCrossRefGoogle Scholar
  11. Forsee WT, Schutzbach JS (1983) Interaction of α-1,2-mannosidase with anionic phospholipids. Eur J Biochem 136:577–582PubMedCrossRefGoogle Scholar
  12. Forsee WT, Jensen JW, Schutzbach JS (1982) Reconstitution and modulation of an α-Mannosidase by phospholipids. Biophys J 37:98–99PubMedCentralPubMedCrossRefGoogle Scholar
  13. Forsee WT, Palmer CF, Schutzbach JS (1989) Purification and characterization of an α-1,2-mannosidase involved in processing asparagine-linked oligosaccharides. J Biol Chem 264:3869–3876PubMedGoogle Scholar
  14. Gabel CA, Bergmann JE (1985) Processing of the asparagine-linked oligosaccharides of secreted and intracellular forms of the vesicular stomatitis virus G protein: in vivo evidence of Golgi apparatus compartmentalization. J Cell Biol 101:460–469PubMedCrossRefGoogle Scholar
  15. Gauss R, Kanehara K, Carvalho P, Ng DT, Aebi M (2011) A complex of Pdi1p and the mannosidase Htm1p initiates clearance of unfolded glycoproteins from the endoplasmic reticulum. Mol Cell 42:782–793PubMedCrossRefGoogle Scholar
  16. Godelaine D, Spiro MJ, Spiro RG (1981) Processing of the carbohydrate units of thyroglobulin. J Biol Chem 256:10161–10168PubMedGoogle Scholar
  17. Gonzalez DS, Karaveg K, Vandersall-Nairn AS, Lal A, Moremen KW (1999) Identification, expression, and characterization of a cDNA encoding human ER mannosidase I, the enzyme that catalyzes the first mannose trimming step in mammalian Asn-linked oligosaccharide biosynthesis. J Biol Chem 274:21375–21386PubMedCrossRefGoogle Scholar
  18. Grondin B, Herscovics A (1992) Topology of ER processing α-mannosidase of Saccharomyces cerevisiae. Glycobiology 2:369–372PubMedCrossRefGoogle Scholar
  19. Hakimi J, Atkinson PH (1982) Glycosylation of intracellular Sindbis virus glycoproteins. Biochemistry 21:2140–2145PubMedCrossRefGoogle Scholar
  20. Hebert DN, Molinari M (2007) In and out of the ER: protein folding, quality control, degradation, and related human diseases. Physiol Rev 87:1377–1408PubMedCrossRefGoogle Scholar
  21. Hebert DN, Molinari M (2012) Flagging and docking: dual roles for N-glycans in protein quality control and cellular proteostasis. Trends Biochem Sci 37:404–410PubMedCentralPubMedCrossRefGoogle Scholar
  22. Hebert DN, Garman SC, Molinari M (2005) The glycan code of the endoplasmic reticulum: asparagine-linked carbohydrates as protein maturation and quality-control tags. Trends Cell Biol 15:364–370PubMedCrossRefGoogle Scholar
  23. Herscovics A (1999a) Glycosidases of the asparagine-linked oligosaccharide processing pathway. In: Pinto BM (ed) Comprehensive natural products chemistry, vol 3. Elsevier, New York, pp 13–35CrossRefGoogle Scholar
  24. Herscovics A (1999b) Processing glycosidases of Saccharomyces cerevisiae. Biochim Biophys Acta 1426:275–285PubMedCrossRefGoogle Scholar
  25. Herscovics A (2001) Structure and function of Class I α1,2-mannosidases involved in glycoprotein synthesis and endoplasmic reticulum quality control. Biochimie 83:757–762PubMedCrossRefGoogle Scholar
  26. Herscovics A, Jelinek-Kelly S (1987) A rapid method for assay of glycosidases involved in glycoprotein biosynthesis. Anal Biochem 166:85–89PubMedCrossRefGoogle Scholar
  27. Herscovics A, Orlean P (1993) Glycoprotein biosynthesis in yeast. FASEB J 7:540–550PubMedGoogle Scholar
  28. Herscovics A, Schneikert J, Athanassiadis A, Moremen KW (1994) Isolation of a mouse Golgi mannosidase cDNA, a member of a gene family conserved from yeast to mammals. J Biol Chem 269:9864–9871PubMedGoogle Scholar
  29. Herscovics A, Romero PA, Tremblay LO (2002) The specificity of the yeast and human class I ER α1,2-mannosidases involved in ER quality control is not as strict previously reported. Glycobiology 12:14G–15GPubMedGoogle Scholar
  30. Hickman S, Theodorakis JL, Greco JM, Brown PH (1984) Processing of MOPC 315 immunoglobulin A oligosaccharides: evidence for endoplasmic reticulum and trans Golgi α1,2-mannosidase activity. J Cell Biol 98:407–416PubMedCrossRefGoogle Scholar
  31. Igdoural SA, Herscovics A, Lal A, Moremen KW, Morales CR, Hermo L (1999) α-Mannosidases involved in N-glycan processing show cell specificity and distinct subcompartmentalization within the Golgi apparatus of cells in the testis and epididymis. Eur J Cell Biol 78:441–452CrossRefGoogle Scholar
  32. Jelinek-Kelly S, Herscovics A (1988) Glycoprotein biosynthesis in Saccharomyces cerevisiae. Purification of the α-mannosidase which removes one specific mannose residue from Man9GlcNAc. J Biol Chem 263:14757–14763PubMedGoogle Scholar
  33. Jelinek-Kelly S, Akiyama T, Saunier B, Tkacz JS, Herscovics A (1985) Characterization of a specific α-mannosidase involved in oligosaccharide processing in Saccharomyces cerevisiae. J Biol Chem 260:2253–2257PubMedGoogle Scholar
  34. Karaveg K, Moremen KW (2005) Energetics of substrate binding and catalysis by class 1 (glycosylhydrolase family 47) α-mannosidases involved in N-glycan processing and endoplasmic reticulum quality control. J Biol Chem 280:29837–29848PubMedCrossRefGoogle Scholar
  35. Karaveg K, Siriwardena A, Tempel W, Liu ZJ, Glushka J, Wang BC, Moremen KW (2005) Mechanism of class 1 (glycosylhydrolase family 47) α-mannosidases involved in N-glycan processing and endoplasmic reticulum quality control. J Biol Chem 280:16197–16207PubMedCrossRefGoogle Scholar
  36. Kedersha NL, Tkacz JS, Berg RA (1985) Characterization of the oligosaccharides of prolyl hydroxylase, a microsomal glycoprotein. Biochemistry 24:5952–5960PubMedCrossRefGoogle Scholar
  37. Kornfeld R, Kornfeld S (1985) Assembly of asparagine-linked oligosaccharides. Annu Rev Biochem 54:631–664PubMedCrossRefGoogle Scholar
  38. Lal A, Schutzbach JS, Forsee WT, Neame PJ, Moremen KW (1994) Isolation and expression of murine and rabbit cDNAs encoding an α1,2-mannosidase involved in the processing of asparagine-linked oligosaccharides. J Biol Chem 269:9872–9881PubMedGoogle Scholar
  39. Lal A, Pang P, Kalelkar S, Romero PA, Herscovics A, Moremen KW (1998) Substrate specificities of recombinant murine Golgi α1, 2- mannosidases IA and IB and comparison with endoplasmic reticulum and Golgi processing α1,2-mannosidases. Glycobiology 8:981–995PubMedCrossRefGoogle Scholar
  40. Leitman J, Ron E, Ogen-Shtern N, Lederkremer GZ (2013) Compartmentalization of endoplasmic reticulum quality control and ER-associated degradation factors. DNA Cell Biol 32:2–7PubMedCrossRefGoogle Scholar
  41. Lipari F, Herscovics A (1994) Production, purification and characterization of recombinant yeast processing α1,2-mannosidase. Glycobiology 4:697–702PubMedCrossRefGoogle Scholar
  42. Lipari F, Herscovics A (1999) Calcium binding to the class I α-1,2-mannosidase from Saccharomyces cerevisiae occurs outside the EF hand motif. Biochemistry 38:1111–1118PubMedCrossRefGoogle Scholar
  43. Lipari F, Gour-Salin BJ, Herscovics A (1995) The Saccharomyces cerevisiae processing α1,2-mannosidase is an inverting glycosidase. Biochem Biophys Res Commun 209:322–326PubMedCrossRefGoogle Scholar
  44. Liscum L, Cummings RD, Anderson RG, DeMartino GN, Goldstein JL, Brown MS (1983) 3-Hydroxy-3-methylglutaryl-CoA reductase: a transmembrane glycoprotein of the endoplasmic reticulum with N-linked “high-mannose” oligosaccharides. Proc Natl Acad Sci USA 80:7165–7169PubMedCentralPubMedCrossRefGoogle Scholar
  45. Mast SW, Moremen KW (2006) Family 47 α-mannosidases in N-glycan processing. Methods Enzymol 415:31–46PubMedCrossRefGoogle Scholar
  46. Mast SW, Diekman K, Karaveg K, Davis A, Sifers RN, Moremen KW (2005) Human EDEM2, a novel homolog of family 47 glycosidases, is involved in ER-associated degradation of glycoproteins. Glycobiology 15:421–436PubMedCrossRefGoogle Scholar
  47. Moremen K (2000) α-Mannosidases in Asparagine-linked oligosaccharide processing and catabolism. In: Ernst B, Hart G, Sinay P (eds) Oligosaccharides in chemistry and biology: a comprehensive handbook, Vol. II: biology of saccharides, Part 1: biosynthesis of glycoconjugates. Wiley, New York, pp 81–117, Vol IIGoogle Scholar
  48. Moremen KW, Molinari M (2006) N-linked glycan recognition and processing: the molecular basis of endoplasmic reticulum quality control. Curr Opin Struct Biol 16:592–599PubMedCrossRefGoogle Scholar
  49. Moremen KW, Touster O (1988) Mannosidases in mammalian glycoprotein processing. In: Das RC, Robbins PW (eds) Protein transfer and organelle biogenesis. Academic, San Diego, pp 209–240Google Scholar
  50. Moremen KW, Trimble RB, Herscovics A (1994) Glycosidases of the asparagine-linked oligosaccharide processing pathway. Glycobiology 4:113–125PubMedCrossRefGoogle Scholar
  51. Pan S, Wang S, Utama B, Huang L, Blok N, Estes MK, Moremen KW, Sifers RN (2011) Golgi localization of ERManI defines spatial separation of the mammalian glycoprotein quality control system. Mol Biol Cell 22:2810–2822PubMedCentralPubMedCrossRefGoogle Scholar
  52. Paulson JC, Colley KJ (1989) Glycosyltransferases : structure, localization, and control of cell type-specific glycosylation. J Biol Chem 264:17615–17618PubMedGoogle Scholar
  53. Rafiq MA, Kuss AW, Puettmann L, Noor A, Ramiah A, Ali G, Hu H, Kerio NA, Xiang Y, Garshasbi M, Khan MA, Ishak GE, Weksberg R, Ullmann R, Tzschach A, Kahrizi K, Mahmood K, Naeem F, Ayub M, Moremen KW, Vincent JB, Ropers HH, Ansar M, Najmabadi H (2011) Mutations in the α1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability. Am J Hum Genet 89:176–182PubMedCentralPubMedCrossRefGoogle Scholar
  54. Rosenfeld MG, Marcantonio EE, Hakimi J, Ort VM, Atkinson PH, Sabatini D, Kreibich G (1984) Biosynthesis and processing of ribophorins in the endoplasmic reticulum. J Cell Biol 99:1076–1082PubMedCrossRefGoogle Scholar
  55. Roth J, Brada D, Lackie PM, Schweden J, Bause E (1990) Oligosaccharide trimming Man9-mannosidase is a resident ER protein and exhibits a more restricted and local distribution than glucosidase II. Eur J Cell Biol 53:131–141PubMedGoogle Scholar
  56. Schutzbach JS, Forsee WT (1990) Calcium ion activation of rabbit liver α1,2-mannosidase. J Biol Chem 265:2546–2549PubMedGoogle Scholar
  57. Tempel W, Karaveg K, Liu ZJ, Rose J, Wang BC, Moremen KW (2004) Structure of mouse Golgia-mannosidase IA reveals the molecular basis for substrate specificity among class 1 (family 47 glycosylhydrolase) α1,2-mannosidases. J Biol Chem 279:29774–29786PubMedCrossRefGoogle Scholar
  58. Tremblay LO, Herscovics A (2000) Characterization of a cDNA encoding a novel human Golgi α1, 2-mannosidase (IC) involved in N-glycan biosynthesis. J Biol Chem 275:31655–31660PubMedCrossRefGoogle Scholar
  59. Tremblay LO, Campbell Dyke N, Herscovics A (1998) Molecular cloning, chromosomal mapping and tissue-specific expression of a novel human α1,2-mannosidase gene involved in N-glycan maturation. Glycobiology 8:585–595PubMedCrossRefGoogle Scholar
  60. Tremblay LO, Nagy Kovacs E, Daniels E, Wong NK, Sutton-Smith M, Morris HR, Dell A, Marcinkiewicz E, Seidah NG, McKerlie C, Herscovics A (2007) Respiratory distress and neonatal lethality in mice lacking Golgi α1,2-mannosidase IB involved in N-glycan maturation. J Biol Chem 282:2558–2566PubMedCrossRefGoogle Scholar
  61. Tulsiani DR, Touster O (1988) The purification and characterization of mannosidase IA from rat liver Golgi membranes. J Biol Chem 263:5408–5417PubMedGoogle Scholar
  62. Tulsiani DR, Hubbard SC, Robbins PW, Touster O (1982) α-d-Mannosidases of rat liver Golgi membranes. Mannosidase II is the GlcNAcMan5-cleaving enzyme in glycoprotein biosynthesis and mannosidases Ia and IB are the enzymes converting Man9 precursors to Man5 intermediates. J Biol Chem 257:3660–3668PubMedGoogle Scholar
  63. Vallee F, Karaveg K, Herscovics A, Moremen KW, Howell PL (2000a) Structural basis for catalysis and inhibition of N-glycan processing class I α1,2-mannosidases. J Biol Chem 275:41287–41298PubMedCrossRefGoogle Scholar
  64. Vallee F, Lipari F, Yip P, Sleno B, Herscovics A, Howell PL (2000b) Crystal structure of a class I α1,2-mannosidase involved in N-glycan processing and endoplasmic reticulum quality control. EMBO J 19:581–588PubMedCrossRefGoogle Scholar
  65. Velasco A, Hendricks L, Moremen KW, Tulsiani DRP, Touster O, Farquhar MG (1993) Cell type-dependent variations in the subcellular distribution of α-mannosidase I and II. J Cell Biol 122:39–51PubMedCrossRefGoogle Scholar
  66. Ziegler FD, Trimble RB (1991) Glycoprotein biosynthesis in yeast: purification and characterization of the endoplasmic reticulum Man9 processing a-mannosidase. Glycobiology 1:605–614PubMedCrossRefGoogle Scholar

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© Springer Japan 2014

Authors and Affiliations

  1. 1.Complex Carbohydrate Research CenterThe University of GeorgiaAthensUSA

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