Rebuild the Biosynthetic Path of Glycans
rebuild_biosynthesis.RdReconstruct the biosynthetic pathway for one or more glycans using enzymatic reactions. This function uses a multi-target breadth-first search to find all feasible pathways that can synthesize all the target glycans.
Arguments
- glycans
A
glyrepr::glycan_structure()vector, or a character vector of strings supported byglyparse::auto_parse(). Can also be a single glycan. If multiple glycans are provided, the starting structure will be decided by the first glycan. Therefore, please make sureglycansare not a mixed vector of N- and O-glycans.- enzymes
A character vector of gene symbols, or a list of
enzyme()objects. IfNULL(default), all available enzymes will be used.- max_steps
Integer, maximum number of enzymatic steps to search. Default is 20.
- filter
Optional function to filter generated glycans at each step. Should take a
glyrepr::glycan_structure()vector as input and return a logical vector of the same length. It will be applied to all the generated glycans at each BFS step for pruning.
Value
An igraph::igraph() object representing the synthesis path(s).
Vertices represent glycan structures with name attribute containing
IUPAC-condensed strings. Edges represent enzymatic reactions with
enzyme attribute containing gene symbols and step attribute
indicating the step number. For multiple targets, the graph includes
all synthesis paths needed to reach every target glycan.
Details
For N-glycans, the starting structure is assumed to be "Glc(3)Man(9)GlcNAc(2)", the N-glycan precursor transfered to Asn by OST. For O-glycans, the starting structure is assumed to be "GalNAc(a1-".
Important notes
Here are some important notes for all functions in the glyenzy package.
Applicability
All algorithms and enzyme information in glyenzy are applicable only to humans, and specifically to N-glycans and O-GalNAc glycans. Results may be inaccurate for other types of glycans (e.g., GAGs, glycolipids) or for glycans in other species (e.g., plants, insects).
Inclusiveness
The algorithm takes an intentionally inclusive approach, assuming that all possible isoenzymes capable of catalyzing a given reaction may be involved. Therefore, results should be interpreted with caution.
For example, in humans, detection of the motif "Neu5Ac(a2-3)Gal(b1-" will return both "ST3GAL3" and "ST3GAL4". In reality, only one of them might be active, depending on factors such as tissue specificity.
Only "concrete" glycans
The function only works for glycans containing concrete residues
(e.g., "Glc", "GalNAc"), and not for glycans with generic
residues (e.g., "Hex", "HexNAc").
Substituents
Subtituents (e.g. sulfation, phosphorylation) is not supported yet,
and the algorithms might fail for glycans with subtituents.
If your glycans contains substituents,
use glyrepr::remove_substituents() to get clean glycans.
Incomplete glycan structures
If the glycan structure is incomplete or partially degraded, the result may be misleading.
Starting points
Throughout glyenzy, the starting glycan is the Glc(3)Man(9)GlcNAc(2) precursor for N-glycans,
and GalNAc(a1- for O-glycans.
This means that enzymes involved in N-glycan precursor biosynthesis, mainly ALGs,
and OST, which transfered the precursor to Asn, are not considered here.
Similarly, GALNTs for O-glycans are not considered.
Examples
library(glyrepr)
library(glyparse)
# Rebuild the biosynthetic pathway of a single glycan
glycan <- "Neu5Ac(a2-3)Gal(b1-4)[Fuc(a1-3)]GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-"
path <- rebuild_biosynthesis(glycan, max_steps = 20)
# Rebuild pathways for multiple glycans
glycans <- c(
"Neu5Ac(a2-3)Gal(b1-4)[Fuc(a1-3)]GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-",
"Gal(b1-4)[Fuc(a1-3)]GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-"
)
path <- rebuild_biosynthesis(glycans, max_steps = 20)
# View the path
igraph::as_data_frame(path, what = "edges")
#> from
#> 1 GalNAc(a1-
#> 2 Gal(b1-3)GalNAc(a1-
#> 3 GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-
#> 4 GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-
#> 5 GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-
#> 6 GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-
#> 7 GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-
#> 8 Gal(b1-4)GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-
#> 9 Gal(b1-4)GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-
#> 10 Gal(b1-4)GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-
#> 11 Gal(b1-4)GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-
#> 12 Fuc(a1-3)[Gal(b1-4)]GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-
#> 13 Fuc(a1-3)[Gal(b1-4)]GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-
#> 14 Fuc(a1-3)[Gal(b1-4)]GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-
#> 15 Neu5Ac(a2-3)Gal(b1-4)GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-
#> 16 Neu5Ac(a2-3)Gal(b1-4)GlcNAc(b1-3)Gal(b1-3)GalNAc(a1-
#> to enzyme step
#> 1 Gal(b1-3)GalNAc(a1- C1GALT1 1
#> 2 GlcNAc(b1-3)Gal(b1-3)GalNAc(a1- B3GNT3 2
#> 3 Gal(b1-4)GlcNAc(b1-3)Gal(b1-3)GalNAc(a1- B4GALT1 3
#> 4 Gal(b1-4)GlcNAc(b1-3)Gal(b1-3)GalNAc(a1- B4GALT2 3
#> 5 Gal(b1-4)GlcNAc(b1-3)Gal(b1-3)GalNAc(a1- B4GALT3 3
#> 6 Gal(b1-4)GlcNAc(b1-3)Gal(b1-3)GalNAc(a1- B4GALT4 3
#> 7 Gal(b1-4)GlcNAc(b1-3)Gal(b1-3)GalNAc(a1- B4GALT5 3
#> 8 Fuc(a1-3)[Gal(b1-4)]GlcNAc(b1-3)Gal(b1-3)GalNAc(a1- FUT3 4
#> 9 Neu5Ac(a2-3)Gal(b1-4)GlcNAc(b1-3)Gal(b1-3)GalNAc(a1- ST3GAL3 4
#> 10 Neu5Ac(a2-3)Gal(b1-4)GlcNAc(b1-3)Gal(b1-3)GalNAc(a1- ST3GAL4 4
#> 11 Neu5Ac(a2-3)Gal(b1-4)GlcNAc(b1-3)Gal(b1-3)GalNAc(a1- ST3GAL6 4
#> 12 Neu5Ac(a2-3)Gal(b1-4)[Fuc(a1-3)]GlcNAc(b1-3)Gal(b1-3)GalNAc(a1- ST3GAL3 5
#> 13 Neu5Ac(a2-3)Gal(b1-4)[Fuc(a1-3)]GlcNAc(b1-3)Gal(b1-3)GalNAc(a1- ST3GAL4 5
#> 14 Neu5Ac(a2-3)Gal(b1-4)[Fuc(a1-3)]GlcNAc(b1-3)Gal(b1-3)GalNAc(a1- ST3GAL6 5
#> 15 Neu5Ac(a2-3)Gal(b1-4)[Fuc(a1-3)]GlcNAc(b1-3)Gal(b1-3)GalNAc(a1- FUT3 5
#> 16 Neu5Ac(a2-3)Gal(b1-4)[Fuc(a1-3)]GlcNAc(b1-3)Gal(b1-3)GalNAc(a1- FUT7 5