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Find a Biosynthesis Path Between Glycan Structures

path_biosynthesis.Rd

Find biosynthetic paths from one glycan structure to another. The default method uses known enzyme rules in a forward breadth-first search. To infer structure-driven paths without enzyme specificity, use path_biosynthesis_virtual().

Usage

path_biosynthesis(
  from,
  to,
  enzymes = NULL,
  max_steps = 10,
  filter = NULL,
  max_virtual_steps = 0L
)

Arguments

from

A glyrepr::glycan_structure() scalar, or a character string supported by glyparse::auto_parse(). The starting glycan structure.

to

A glyrepr::glycan_structure() scalar, or a character string supported by glyparse::auto_parse(). The target glycan structure.

enzymes

A character vector of concrete gene symbols or abstract activity names, or a list of enzyme() objects. Concrete and abstract enzymes cannot be mixed. If NULL (default), all available concrete enzymes will be used.

max_steps

Integer, maximum number of enzymatic steps to search. Default is 10.

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 filters generated products.

max_virtual_steps

Integer, maximum number of target-directed virtual enzyme steps allowed when no fully enzymatic path exists. Default is 0L, which disables virtual fallback. See the "Virtual fallback" section for more details.

Value

A glyenzy_biosynthesis_network object inheriting from igraph::igraph() and representing the synthesis path(s). Vertices represent glycan structures, with IUPAC-condensed strings in the name attribute and a logical target attribute indicating the target glycan. At most one directed edge connects each substrate and product. Every edge has an integer step, a logical is_virtual, a scalar display label in enzyme, and a list-valued enzymes attribute containing concrete enzyme candidates. For known reactions, enzyme combines the candidates with " / "; for virtual reactions, it contains the structural virtual-enzyme name and enzymes is empty unless concrete candidates were annotated.

Important notes

Here are some important notes for all functions in the glyenzy package.

Applicability

Known-enzyme algorithms and enzyme information in glyenzy are applicable only to humans. Curated coverage is strongest for N-glycans and O-glycans and also includes selected glycosphingolipid headgroups and other glycan contexts. Lipid and protein aglycones are not represented, so glycolipid rules model the carbohydrate headgroup with ceramide omitted. Results may be inaccurate for unsupported glycan contexts or 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.

Concrete glycans by default

Most functions only work for glycans containing concrete residues (e.g., "Glc", "GalNAc"), and not for glycans with generic residues (e.g., "Hex", "HexNAc"). Inputs with generic residues are supported where explicitly documented, such as trace_biosynthesis() and path_biosynthesis().

Substituents

Sulfate substituents are supported. Other substituents, such as phosphorylation and methylation, are not supported. Use glyrepr::remove_substituents() when unsupported substituents are present.

Incomplete or non-concrete glycan structures

Some functions accept glycan structures that are incomplete, partially degraded, or contain generic residues. When accepted, glycans with a glyrepr::get_structure_level() other than "intact", or with a glyrepr::get_mono_type() other than "concrete", are matched with the lenient motif matching mode in glymotif. A warning is raised because enzyme predictions may be less reliable.

Starting points

For known-enzyme path inference:

  • For N-glycans, the starting structure is assumed to be "Glc(3)Man(9)GlcNAc(2)", the N-glycan precursor transferred to Asn by OST.

  • For O-GalNAc glycans, the starting structure is assumed to be "GalNAc(a1-".

  • For O-GlcNAc glycans, the starting structure is assumed to be "GlcNAc(b1-".

  • For O-Man glycans, the starting structure is assumed to be "Man(a1-".

  • For O-Fuc glycans, the starting structure is assumed to be "Fuc(a1-".

  • For O-Glc glycans, the starting structure is assumed to be "Glc(b1-".

  • For GlcCer glycans, the starting structure is assumed to be "Glc(b1-",

  • For GalCer glycans, the starting structure is assumed to be "Gal(b1-"

Input compatibility

trace_biosynthesis(), trace_biosynthesis_virtual(), path_biosynthesis(), and path_biosynthesis_virtual() accept only glycans that share one monosaccharide type ("concrete" or "generic") and one structure level ("intact" or "topological"). Structures with mixed generic and concrete residues, partial structures, and missing structures are not supported. In the path_*() functions, from and to must have the same monosaccharide type and structure level.

Use glyrepr::convert_to_generic() to standardize monosaccharide types or glyrepr::remove_linkages() to standardize structures at the topological level.

Virtual fallback

Sometimes the biosynthesis network of a glycan cannot be fully resolved; i.e., some enzymatic steps are not inferred to be catalyzed by any known enzyme ("bad" steps). By default, an error is raised for these glycans.

max_virtual_steps provides a fallback for these glycans. For a "bad" step, a virtual enzyme is assigned to allow the algorithm to continue. For example, for the O-GalNAc core 5 "GalNAc(a1-3)GalNAc(a1-", an "a3GalNAcT" is assigned to the step that adds the a3 GalNAc. Unsupported sulfate additions similarly use "3SulfoT", "6SulfoT", or "?SulfoT".

Therefore, max_virtual_steps can also be interpreted as "the maximum number of glycosidic bonds or sulfate transfers that cannot be assigned by a known enzyme." Increasing this number loosens the criteria.

Examples

library(glyrepr)
library(glyparse)

# Find shortest path
from <- "Gal(b1-4)GlcNAc(b1-"
to <- "Neu5Ac(a2-6)Gal(b1-4)GlcNAc(b1-"
path <- path_biosynthesis(from, to, enzymes = "ST6GAL1", max_steps = 3)

# View the path
igraph::as_data_frame(path, what = "edges")
#>                  from                              to  enzyme is_virtual step
#> 1 Gal(b1-4)GlcNAc(b1- Neu5Ac(a2-6)Gal(b1-4)GlcNAc(b1- ST6GAL1      FALSE    1
#>   enzymes
#> 1 ST6GAL1