RHEA → GO Contribution & Gap Project

SCOPING PIPELINE

RHEA → GO Contribution & Gap Project

Overview

This project examines the RHEA reaction database as a source of GO molecular-
function annotations, in the same spirit as the SPKW (UniProt
keywords) and UniPathway source-audit projects. RHEA reaches GO
through the public rhea2go mapping; in GOA these annotations appear as
GO_REF:0000116, assigned_by=RHEA, aspect molecular_function, evidence
IEA. GO_REF:0000116 is the RHEA counterpart of SPKW's GO_REF:0000043 and
EC2GO's GO_REF:0000003.

Unlike SPKW and UniPathway, RHEA is a molecular-function source (enzymatic
reactions), so the analysis runs in two complementary directions:

  1. Contribution (forward). Where is GO_REF:0000116 the unique
    (closure-filtered) source of an enzyme-activity annotation, and are those
    contributions useful or over-/mis-propagated? — the SPKW-style audit.
  2. Gaps (reverse). Where does a UniProtKB entry carry a catalytic activity
    with a RHEA cross-reference, but the GO molecular-function term that
    rhea2go maps that reaction to never propagates into GOA? These are
    annotations that "fall through the cracks" — curation gap-filling
    opportunities rather than over-annotations.

See RHEA-METHODOLOGY.md for the queries, the
reproducible probe script, and the all-important closure caveat. The deeper
EC-masking and specificity analysis lives in
RHEA-EC-SPECIFICITY.md.

Key Findings (scoping pass)

RHEA is mostly masked by EC

UniProt enzymes almost always carry both an EC number and a RHEA reaction,
and EC also reaches GO — via ec2go (GO_REF:0000003). So RHEA's GO_REF:0000116
contribution is only "real" where EC2GO did not already supply the same term.
Computed live from rhea2go, ec2go, and the RHEA REST API
(rhea_ec_specificity.py):

So most GO_REF:0000116 volume is redundant with EC2GO and would be dropped by
the closure-filtered uniqueness query. RHEA's genuine value is the 772
RHEA-only terms, the 462 EC-without-ec2go reactions, the 118
differing-term reactions, and the reverse-propagation gap below.

Specificity cuts both ways

Full tables and examples: RHEA-EC-SPECIFICITY.md.

Reverse-Gap Pilot (live, exact-match)

Reviewed-only UniProtKB entries carrying each reaction, and how many lack the
rhea2go-mapped GO molecular-function term. Generated with
rhea_go_gap_probe.py (--gap-sample).
pct_missing is an exact-match upper bound — see the closure caveat below.

RHEA Mapped GO MF term N reviewed N missing (exact) % missing Note
RHEA:21248 GO:0034062 5'-3' RNA polymerase activity ≥500 497 ~99% capped at 500; striking — generic parent rarely used directly
RHEA:10596 GO:0004713 protein tyrosine kinase activity ≥500 198 ~40% capped at 500; many entries carry specific RTK children
RHEA:13065 GO:0016887 ATP hydrolysis activity ≥500 33 ~7% capped at 500
RHEA:15421 GO:0004467 long-chain fatty acid-CoA ligase activity 90 2 ~2% clean propagation
RHEA:16505 GO:0008813 chorismate lyase activity 148 0 0% clean propagation
RHEA:11628 GO:0004737 pyruvate decarboxylase activity 33 0 0% clean propagation
RHEA:22636 GO:0047840 dCTP diphosphatase activity 49 0 0% clean propagation
RHEA:46608 (no rhea2go mapping) — — — "no GO term" gap class → candidate new term

Reading the pilot. The clean 0–2% reactions show the pipeline works well for
specific, single-product enzyme activities. The high-gap reactions
(RHEA:21248, RHEA:10596) are exactly the generic-parent reactions where
rhea2go points at a broad activity term that curated entries express via more
specific children — so most of that 40–99% is expected closure coverage, not a
genuine missing annotation. The job of the closure-filtered follow-up is to
separate the residual true gaps (entries with neither the parent nor any
child) from this expected altitude difference.

Mapping Gaps Found

# Gap Size What it is
G1 EC-masking redundancy 4,324 reactions (88%) RHEA's GO term duplicates one EC2GO already supplies → low marginal value
G2 RHEA-only GO terms 772 terms Reachable via rhea2go but not ec2go — RHEA's unique forward contribution
G3 EC-without-ec2go 462 reactions EC has no ec2go line → RHEA is the only EC-adjacent GO route
G4 No-rhea2go enzymatic reactions 2,731 / 7,635 (36%) Genuine enzymatic reaction with no GO MF target (2,445 EC-level; 286 specific-reaction-only)
G5 Specificity-collapse 679 terms, up to 67:1 GO lacks substrate-specific MF children → many reactions flatten to one term
G6 Reverse-propagation gap pilot below UniProt RHEA annotations whose mapped GO term never reaches GOA

Worked case reviews of this gap on real Swiss-Prot enzymes — where a RHEA
reaction has no rhea2go mapping and the GO molecular function is missing or
only a class root — are in RHEA-GAP-CASES.md: PHYKPL
(MF = only lyase activity; propose new term), B3GALNT2 (class-level
GalNAc-T; propose new term; dystroglycanopathy gene), SAMD8/SMSr (the
existing term GO:0002950 ceramide phosphoethanolamine synthase activity is
simply not applied — pure propagation gap), and SULT6B1 (only
sulfotransferase activity; cautious fill given by-similarity evidence). Cases
selected reproducibly by rhea_gap_finder.py.

G1/G4 are mirror images: where EC and RHEA agree RHEA is redundant; where RHEA
has no GO term EC usually still carries the protein at coarser EC granularity —
so most gaps are specificity gaps (right activity, coarse GO representation),
not coverage gaps (no MF term at all). G2/G3/G6 are where RHEA genuinely adds
something EC does not. Detail and reproduction in
RHEA-EC-SPECIFICITY.md.

Curated new mappings (SSSOM)

Filling the gaps is a curation deliverable, not just an audit. The curated
RHEA→GO mappings — reactions absent from rhea2go but with (or needing) a GO MF
term — are recorded in rhea2go.sssom.yaml, the same
SSSOM YAML format used by the ANTIMICROBIAL_RESISTANCE
aro2go mapping set. 132 mappings so far, each backed by a review of a reviewed
(Swiss-Prot) enzyme that carries the reaction
(RHEA-MAPPING-REVIEWS.md). The predicate encodes
the specificity finding:

Every GO id/label is verified non-obsolete against QuickGO; every RHEA id +
equation comes from the UniProt catalytic-activity line; every backing enzyme is
reviewed (mostly PE1, with catalytic-activity PMIDs). Validate with
just validate-rhea-mappings — SSSOM structural validation plus GO term/label
validation (GO objects bound to the molecular-function branch; generated nested
view rhea2go.terms.yaml).

Propagation gain. If these mappings were added to rhea2go, they would
add 42 new GO molecular-function annotations to Swiss-Prot (reviewed) entries — the
curation-relevant gain we track — filling real reviewed-entry gaps; the all-UniProtKB figure
(~25,842, mostly automated TrEMBL) is secondary because curated enzymes already carry the term,
because reviewed enzymes carrying the reaction already have the term (the
EC-masking result at the annotation level). See
RHEA-ANNOTATION-GAIN.md
(rhea_annotation_gain.py).

Methods

GO_REF:0000116 identification and the rhea2go mapping statistics were
computed live (GO release 2026-05-19). The reverse-gap pilot was computed live
against the UniProtKB REST API (rhea:<id> query field, reviewed:true).

The forward contribution audit reuses the closure-filtered uniqueness query
from UniPathway/SPKW, swapping the
reference id to GO_REF:0000116. That cross-organism scan needs the local
~/repos/go-db/db/*.ddb DuckDBs, which are not present in the web container,
so the UNIPATHWAY-style contribution table is staged, not yet populated (see
Follow-Up Targets). The reverse-gap probe needs no go-db and runs anywhere with
network access.

Full queries, the probe script, and the mandatory closure caveat are in
RHEA-METHODOLOGY.md.

How this differs from SPKW and UniPathway

SPKW (GO_REF:0000043) UniPathway (GO_REF:0000041) RHEA (GO_REF:0000116)
GO aspect mostly BP (+ some MF/CC) mostly BP (pathways) MF (enzyme activity)
Dominant failure mode process conflation / "expression ≠ function" broad pathway-bucket propagation parent-vs-child altitude; wrong-substrate paralog
Direction of interest over-annotation (remove/modify) mostly contribution audit both: contribution and reverse gap-filling
Source status retired by GOA (~Apr 2026) for cellular organisms archived/legacy vocabulary active, curated, reaction-grounded

The RHEA source is better grounded than SPKW (a reaction is a precise
biochemical claim), so the expected verdict skew is toward ACCEPT /
KEEP_AS_NON_CORE on the forward side and toward NEW / gap-filling on the
reverse side — the opposite emphasis from the SPKW over-annotation hunt.

Curation Recommendations (preliminary)

  1. Treat the gap direction as the high-value half. Unlike SPKW, RHEA's main
    contribution is finding correct enzyme activities that GO is missing, not
    removing over-annotations. Prioritise reactions with a high closure-filtered
    gap.
  2. Always closure-filter before calling a gap. Exact-match gap percentages
    are upper bounds; subtract entries carrying any descendant of the mapped term
    (the SPKW/UniPathway closure pattern) before proposing additions.
  3. Generic-parent reactions deserve altitude review. Where rhea2go maps a
    reaction to a broad activity term (e.g. protein tyrosine kinase activity),
    prefer the specific child the curated entry already supports; the parent is
    often redundant.
  4. Reactions with no rhea2go line are proposed_new_terms candidates — a
    real UniProt-annotated activity with no GO MF target to land on.
  5. Forward-unique RHEA rows are usually keepers. A closure-unique
    GO_REF:0000116 activity term is a precise biochemical assertion; the review
    risk is wrong-substrate/wrong-paralog specificity, not process conflation.

Follow-Up Targets

Target Rationale
Forward closure-filtered cross-organism scan (GO_REF:0000116) The UNIPATHWAY-style contribution table; needs go-db DuckDBs. Quantifies where RHEA is the unique MF source.
Closure-aware reverse gap on the high-gap pilot reactions Separate true gaps from expected parent/child altitude for RHEA:21248, RHEA:10596; promote real gaps to gene reviews.
"No rhea2go mapping" reaction set Enumerate UniProt-used RHEA reactions with no GO MF target → batch proposed_new_terms.
RHEA directional-quartet join audit Test whether master-vs-directional id mismatch causes systematic non-propagation.
Exemplar gene reviews Pick 2–3 confirmed (closure-filtered) gap genes and run the full review workflow, mirroring the UniPathway exemplar pattern.

Project Status