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Difference between revisions of "Glycosyltransferase Family 108"

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#Holmes2005 2B4W, Hypothetical protein from ''Leishmania major'' [http://www.rcsb.org/structure/2B4W].
 
#Holmes2005 2B4W, Hypothetical protein from ''Leishmania major'' [http://www.rcsb.org/structure/2B4W].
  
#Sernee2019 pmid= 31513773
+
#Sernee2019 pmid=31513773
  
 
#Nakae2013 pmid=23954514
 
#Nakae2013 pmid=23954514

Revision as of 16:21, 17 September 2019

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Glycosyltransferase Family GT108
Clan GT-x
inverting: GDP-Man β-1,2-mannosyltransferase (EC 2.4.99.-), donor is GDP-α-Man; 1,2-β-oligomannan phosphorylase (EC 2.4.1.340), product is α-mannose-1-phosphate
Active site residues known
CAZy DB link
http://www.cazy.org/GT108.html


Substrate specificities

The glycosyltransferases in family GT108 were originally identified by bioinformatics analysis using GH130 sequences as a query. This identified a tandem repeat of seven genes on chromosome 10 of Leishmania mexicana and varying numbers of orthologs in other trypanosomatids [1]. A null mutant lacking the entire array of seven genes lost the ability to synthesize 1,2-β-oligomannan (termed mannogen). These enzymes were termed mannosyltransferase/phosphorylases (MTPs) owing to ability to both synthesize mannogen from GDPMan and/or Man-1-P, as well as an ability to catalyze phosphorolysis of mannogen to form Man-1-P. Specifically, the L. mexicana enzymes MPT3, MPT4, MPT6 and MPT7 catalyzed the phosphorolysis of mannogen to give Man-1-P, as well as the reverse reaction to synthesize mannogen by mannosyltransfer from Man-1-P. The ‘’L. Mexicana’’ enzymes MPT1 and MPT2 act as GDP-Man dependent β-1,2-mannosyltransferases, elongating mannogen, and lack detectable phosphorolytic activity.

Kinetics and Mechanism

In the glycoside cleavage reaction this residue acts as a general acid, protonating the glycosidic leaving group via a proton relay through the -1 subsite mannose 3-OH, allowing phosphate to displace the anomeric glycoside leaving group. In the reverse reaction involving mannosyl transfer from Man-1-P (or GDP-Man for MPT1 and 2), this residue acts as a general base, deprotonating the 2-OH of the sugar nucleophile to promote glycosidic bond formation. The proposed mechanism is similar to that for family GH130 β-1,2-mannoside phosphorylases [2]

Catalytic Residues

Asp83 is the catalytic general base in the Leishmania mexicana MPT4 [1]. The GDP-Man transferases MTP1 and MTP2 contain a His residue (His168 in MTP1 and His161 in MTP2) in the active site; at the equivalent position the phosphorolytic MTPs such as MTP4 contain an Arg residue (Arg150) [1].

Three-dimensional structures

The three-dimensional structures of several GT108 proteins have been reported. The Structural Genomics of Pathogenic Protozoa Consortium (SGPP) deposited the first structure of a member of this family as a 'hypothetical protein' from L. major [3]; the function of this protein remains unknown. The structures of several MPTs from L. mexicana have been reported. All proteins have a five-bladed β-propeller fold. Similar folds are predicted for other family members.

Family Firsts

First catalytic residue identification
Asp83 in Leishmania mexicana MPT4 and other MPT enzymes [1]. The His/Arg switch distinguishing GDP-Man dependent transferase activity, and phosphorolytic activity was also identified in this study.
First 3-D structure
The Leishmania major strain Friedlin protein LMJF_10_1260 was determined by X-ray crystallography [3].

References

  1. Sernee MF, Ralton JE, Nero TL, Sobala LF, Kloehn J, Vieira-Lara MA, Cobbold SA, Stanton L, Pires DEV, Hanssen E, Males A, Ward T, Bastidas LM, van der Peet PL, Parker MW, Ascher DB, Williams SJ, Davies GJ, and McConville MJ. (2019) A Family of Dual-Activity Glycosyltransferase-Phosphorylases Mediates Mannogen Turnover and Virulence in Leishmania Parasites. Cell Host Microbe. 26, 385-399.e9. DOI:10.1016/j.chom.2019.08.009 | PubMed ID:31513773 | HubMed [Sernee2019]
  2. Nakae S, Ito S, Higa M, Senoura T, Wasaki J, Hijikata A, Shionyu M, Ito S, and Shirai T. (2013) Structure of novel enzyme in mannan biodegradation process 4-O-β-D-mannosyl-D-glucose phosphorylase MGP. J Mol Biol. 425, 4468-78. DOI:10.1016/j.jmb.2013.08.002 | PubMed ID:23954514 | HubMed [Nakae2013]
  3. 2B4W, Hypothetical protein from Leishmania major [1].
    [Holmes2005]
All Medline abstracts: PubMed | HubMed