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Trace a Virtual Biosynthetic Path of Glycans

trace_biosynthesis_virtual.Rd

Reconstruct every structure-driven biosynthetic path for one or more glycans by trimming terminal residues and sulfate groups backward. Unlike trace_biosynthesis(), this does not require known enzyme rules.

Usage

trace_biosynthesis_virtual(glycans, enzymes = NULL, annotate_enzymes = FALSE)

Arguments

glycans

A glyrepr::glycan_structure() vector, or a character vector of strings supported by glyparse::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 sure glycans are not of mixed glycan types.

enzymes

A character vector of gene symbols, or a list of enzyme() objects. Used only when annotate_enzymes is TRUE; if NULL, all available enzymes are considered.

annotate_enzymes

Whether to annotate each virtual transition with concrete enzymes whose rules can perform it. Defaults to FALSE.

Value

A glyenzy_virtual_biosynthesis_network object inheriting from glyenzy_biosynthesis_network and igraph::igraph(). Vertices contain IUPAC-condensed strings in name and a logical target attribute indicating whether each vertex is a target glycan; edges have a forward step and virtual-enzyme enzyme attribute. When annotate_enzymes is TRUE, concrete_enzymes is a list of character vectors containing every candidate concrete enzyme for each transition.

Virtual enzymes

Each edge is named for the residue added by that step. Intact glycans include the linkage anomer and acceptor position, so a beta-1,4-linked GlcNAc is labeled "b4GlcNAcT". Partial and topological glycans omit linkage information and use "GlcNAcT". Generic or mixed topological glycans use their preserved generic residue names, such as "HexNAcT".

Sulfation is represented as its own atomic transition. Sulfate additions at positions 3 and 6 use "3SulfoT" and "6SulfoT"; an unknown or other position uses "?SulfoT". A sulfated terminal residue is therefore desulfated before the residue itself can be trimmed.

Virtual tracing starts N-glycans at the N-glycan core and all other glycans at their reducing-end root residue. Sulfates are removed from these automatically selected starts. In path_biosynthesis_virtual(), the explicit from glycan is always the virtual starting structure, including any sulfate groups it contains; those sulfates must also occur in to. These networks represent structural possibilities rather than biological feasibility.

Generic structures do not retain glycan-class metadata. A generic structure matching the N-glycan-core topology is therefore assumed to be an N-glycan; use path_biosynthesis_virtual() with an explicit from when that topology belongs to another glycan class.

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 or mixed 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

If the glycan structure is incomplete, partially degraded, or contains generic or mixed residues, the result may be misleading. 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-"

Examples

library(glyrepr)
library(glyparse)

virtual_path <- trace_biosynthesis_virtual(
  "GlcNAc(b1-4)Gal(b1-3)GalNAc(a1-"
)

annotated_path <- trace_biosynthesis_virtual(
  "GlcNAc(b1-4)Gal(b1-3)GalNAc(a1-",
  annotate_enzymes = TRUE
)