Glycosyltransferase
Glycosyltransferases (GTFs, Gtfs) are
The result of glycosyl transfer can be a
Glycosyltransferases that use sugar nucleotide donors are Leloir enzymes, after
Mammals use only 9 sugar nucleotide donors for glycosyltransferases:
Many glycosyltransferases are
Mechanism
Glycosyltransferases can be segregated into "retaining" or "inverting" enzymes according to whether the stereochemistry of the donor's anomeric bond is retained (α→α) or inverted (α→β) during the transfer. The inverting mechanism is straightforward, requiring a single nucleophilic attack from the accepting atom to invert stereochemistry.
The retaining mechanism has been a matter of debate, but there exists strong evidence against a double displacement mechanism (which would cause two inversions about the anomeric carbon for a net retention of stereochemistry) or a dissociative mechanism (a prevalent variant of which was known as SNi). An "orthogonal associative" mechanism has been proposed which, akin to the inverting enzymes, requires only a single nucleophilic attack from an acceptor from a non-linear angle (as observed in many crystal structures) to achieve anomer retention.[4]
Reaction reversibility
The recent discovery of the reversibility of many reactions catalyzed by inverting glycosyltransferases served as a paradigm shift in the field and raises questions regarding the designation of sugar nucleotides as 'activated' donors.[5][6][7][8][9]
Classification by sequence
Sequence-based classification methods have proven to be a powerful way of generating hypotheses for protein function based on sequence alignment to related proteins. The carbohydrate-active enzyme database presents a sequence-based classification of glycosyltransferases into over 90 families.[10] The same three-dimensional fold is expected to occur within each of the families.[11]
Structure
In contrast to the diversity of 3D structures observed for
Inhibitors
Many inhibitors of glycosyltransferases are known. Some of these are natural products, such as
Determinant of blood type
Glycosyltransferase family 6 | |||||||||
---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||
Symbol | GT6 | ||||||||
Pfam | PF03414 | ||||||||
InterPro | IPR005076 | ||||||||
OPM superfamily | 199 | ||||||||
OPM protein | 2rj6 | ||||||||
Membranome | 468 | ||||||||
|
The ABO blood group system is determined by what type of glycosyltransferases are expressed in the body.
The ABO
The combination of glycosyltransferases by both alleles present in each person determines whether there is an AB, A, B or O blood type.
Uses
Glycosyltransferases have been widely used in both the targeted synthesis of specific glycoconjugates as well as the synthesis of differentially glycosylated libraries of drugs, biological probes or natural products in the context of drug discovery and drug development (a process known as glycorandomization).[17] Suitable enzymes can be isolated from natural sources or produced recombinantly. As an alternative, whole cell-based systems using either endogenous glycosyl donors or cell-based systems containing cloned and expressed systems for synthesis of glycosyl donors have been developed. In cell-free approaches, the large-scale application of glycosyltransferases for glycoconjugate synthesis has required access to large quantities of the glycosyl donors. On the flip-side, nucleotide recycling systems that allow the resynthesis of glycosyl donors from the released nucleotide have been developed. The nucleotide recycling approach has a further benefit of reducing the amount of nucleotide formed as a by-product, thereby reducing the amount of inhibition caused to the glycosyltransferase of interest – a commonly observed feature of the nucleotide byproduct.
See also
- Carbohydrate chemistry
- Chemical glycosylation
- Glucuronosyltransferase
- Glycogen synthase
- Glycosyl acceptor
- Glycosyl donor
- Glycosylation
- Oligosaccharyltransferase
References
- PMID 18990828.
- ISBN 978-0-87969-770-9.
- ^ Transferases in Membranome database.
- PMID 23936487.
- S2CID 38072017.
- PMID 17177349.
- S2CID 45058028.
- PMID 18798210.
- PMID 21857660.
- ^ CAZypedia Glycosyltransferases
- ^ CAZy Glycosyl Transferase
- PMID 22688446.
- PMID 21592771.
- ^ SCOP: Structural Classification of Proteins
- S2CID 41658295.
- PMID 32312486.
- PMID 21901218.