View source for Glycoside Hydrolase Family 38

* [[Author]]: [[User:David Rose|David Rose]]
* [[Responsible Curator]]:  [[User:David Rose|David Rose]]
----

<div style="float:right">
{| {{Prettytable}} 
|-
|{{Hl2}} colspan="2" align="center" |'''Glycoside Hydrolase Family GH38'''
|-
|'''Clan'''    
|GH-x
|-
|'''Mechanism'''
|retaining
|-
|'''Active site residues'''
|known
|-
|{{Hl2}} colspan="2" align="center" |'''CAZy DB link'''
|-
| colspan="2" |http://www.cazy.org/fam/GH38.html
|}
</div>

== Substrate specificities ==
GH38 enzymes are Class II &alpha;-mannosidases. They range in breadth of specificity from the Golgi &alpha;-mannosidase (2A1), which has a dual specificity for &alpha;1,6 and &alpha;1,3-linked mannoses, to the lysosomal mannosidases, which have either broad (2B1 cleaves &alpha;1,2, &alpha;1,3 and &alpha;1,6 linkages) or narrow specificities (2B2 is specific for &alpha;1,6). GH38 active sites can be quite long and open, and some are sensitive to the polysaccharide substrate structure. For example, Golgi &alpha;-mannosidase II requires the presence of a GlcNAc residue some five residues away from the cleavage site, while lysosomal mannosidases do not have that requirement <cite>1 11</cite>. 
There have been GH38 mannosidases identified in a number of different localizations, classed into subfamilies with different substrate specificities and biochemical properties, and, presumably, different physiological roles. The Golgi enzyme is identified as 2A1 (Class 2, A for Golgi, enzyme 1). Lysosomal GH38 mannosidases are indicated by 'B' (2B1, 2B2) and those likely existing in the cytoplasm by 'C'. 
Physiological roles have been identified for the Golgi enzyme in the protein N-glycosylation pathway and lysosomal mannosidases in general are likely to be involved in scavenging of degraded glycoproteins. Roles for the cytoplasmic subclass have not been identified definitively, but they may play a role in protein recognition or signalling.

== Kinetics and Mechanism ==
GH38 enzymes operate by the conventional Koshland double-displacement retaining mechanism. This was initially determined by covalent intermediate trapping with the Jack Bean homologue <cite>3</cite> and later confirmed by structural analysis of covalent intermediates <cite>5</cite>

== Catalytic Residues ==
Both catalytic side chains are Asp residues. The nucleophile Asp204 (Golgi &alpha;-mannosidase II numbering) was inferred from previous studies with Jack Bean mannosidase <cite>3</cite> and confirmed in the crystal structures of covalent intermediates <cite>2</cite>. Mutagenesis studies implicated Asp341 as the likely acid-base catalyst. 

== Three-dimensional structures ==
The crystal structure of the GH38 domain of ''Drosophila'' Golgi &alpha;-mannosidase II <cite>1</cite> has been determined in complex with a large number of inhibitors and catalytic intermediate mimics. Many of these are at very high resolution: 1.2-1.6&Aring; (see <cite>5 6 7 8 9</cite> for examples). An enzyme-substrate complex has also been determined <cite>10</cite>.
The crystal structure of bovine lysosomal &alpha;-mannosidase II was determined to 2.7&Aring; resolution indicated interesting low-pH activation effects <cite>4</cite> .
The GH38 fold has been referred to as the "mannosidase fold". It is one large (approximately 1000-residue) globular domain, which can be roughly divided by secondary structure into an &alpha;/&beta; portion and an all-&beta; region. The former portion contains the active site, anchored by a Zn atom, which forms an integral part of the -1 site, interacting with the saccharide and helping to induce substrate distortion <cite>1</cite>.

== Family Firsts ==
;First sterochemistry determination: 
;First catalytic nucleophile identification: Jack Bean mannosidase <cite>3</cite> 
;First general acid/base residue identification: Golgi &alpha;-mannosidase II covalent intermediate stabilization <cite>2</cite> 
;First 3-D structure: Golgi &alpha;-mannosidase II <cite>1</cite> 

== References ==
<biblio>
#1 pmid=11406577 
#2 pmid=12960159
#3 pmid=9442045
#4 pmid=12634058
#5 pmid=14636047
#6 pmid=16787095
#7 pmid=18076078 
#8 pmid=18558690
#9 pmid=18599296
#10 pmid=18599462
#11 pmid=16115860

</biblio>

<!-- DO NOT REMOVE THIS CATEGORY TAG! (...but please delete the nowiki tags before saving.) -->
[[Category:Glycoside Hydrolase Families|GH038]]