[Feature] EnzymeLink Annotations (#152)

Co-authored-by: Tim Lorsbach <tim@lorsba.ch>
Reviewed-on: enviPath/enviPy#152

epdb/logic.py

@@ -26,6 +26,7 @@ from epdb.models import (
     Compound,
     Reaction,
     CompoundStructure,
+    EnzymeLink,
 )
 from utilities.chem import FormatConverter
 from utilities.misc import PackageImporter, PackageExporter
@@ -617,6 +618,8 @@ class PackageManager(object):
         parent_mapping = {}
         # Mapping old scen_id to old_obj_id
         scen_mapping = defaultdict(list)
+        # Enzymelink Mapping rule_id to enzymelink objects
+        enzyme_mapping = defaultdict(list)
 
         # Store Scenarios
         for scenario in data["scenarios"]:
@@ -648,9 +651,7 @@ class PackageManager(object):
                 # Broken eP Data
                 if name == "initialmasssediment" and addinf_data == "missing data":
                     continue
-
+                if name == "columnheight" and addinf_data == "(2)-(2.5);(6)-(8)":
-                # TODO Enzymes arent ready yet
-                if name == "enzyme":
                     continue
 
                 try:
@@ -740,6 +741,9 @@ class PackageManager(object):
             for scen in rule["scenarios"]:
                 scen_mapping[scen["id"]].append(r)
 
+            for enzyme_link in rule.get("enzymeLinks", []):
+                enzyme_mapping[r.uuid].append(enzyme_link)
+
         print("Par: ", len(par_rules))
         print("Seq: ", len(seq_rules))
 
@@ -757,6 +761,9 @@ class PackageManager(object):
             for scen in par_rule["scenarios"]:
                 scen_mapping[scen["id"]].append(r)
 
+            for enzyme_link in par_rule.get("enzymeLinks", []):
+                enzyme_mapping[r.uuid].append(enzyme_link)
+
             for simple_rule in par_rule["simpleRules"]:
                 if simple_rule["id"] in mapping:
                     r.simple_rules.add(SimpleRule.objects.get(uuid=mapping[simple_rule["id"]]))
@@ -777,6 +784,9 @@ class PackageManager(object):
             for scen in seq_rule["scenarios"]:
                 scen_mapping[scen["id"]].append(r)
 
+            for enzyme_link in seq_rule.get("enzymeLinks", []):
+                enzyme_mapping[r.uuid].append(enzyme_link)
+
             for i, simple_rule in enumerate(seq_rule["simpleRules"]):
                 sro = SequentialRuleOrdering()
                 sro.simple_rule = simple_rule
@@ -910,6 +920,39 @@ class PackageManager(object):
 
         print("Scenarios linked...")
 
+        # Import Enzyme Links
+        for rule_uuid, enzyme_links in enzyme_mapping.items():
+            r = Rule.objects.get(uuid=rule_uuid)
+            for enzyme in enzyme_links:
+                e = EnzymeLink()
+                e.uuid = UUID(enzyme["id"].split("/")[-1]) if keep_ids else uuid4()
+                e.rule = r
+                e.name = enzyme["name"]
+                e.ec_number = enzyme["ecNumber"]
+                e.classification_level = enzyme["classificationLevel"]
+                e.linking_method = enzyme["linkingMethod"]
+                e.save()
+
+                for reaction in enzyme["reactionLinkEvidence"]:
+                    reaction = Reaction.objects.get(uuid=mapping[reaction["id"]])
+                    e.reaction_evidence.add(reaction)
+
+                for edge in enzyme["edgeLinkEvidence"]:
+                    edge = Edge.objects.get(uuid=mapping[edge["id"]])
+                    e.reaction_evidence.add(edge)
+
+                for evidence in enzyme["linkEvidence"]:
+                    matches = re.findall(r">(R[0-9]+)<", evidence["evidence"])
+                    if not matches or len(matches) != 1:
+                        logger.warning(f"Could not find reaction id in {evidence['evidence']}")
+                        continue
+
+                    e.add_kegg_reaction_id(matches[0])
+
+                e.save()
+
+        print("Enzyme links imported...")
+
         print("Import statistics:")
         print("Package {} stored".format(pack.url))
         print("Imported {} compounds".format(Compound.objects.filter(package=pack).count()))

epdb/management/commands/localize_urls.py

@@ -41,6 +41,7 @@ class Command(BaseCommand):
             "RuleBasedRelativeReasoning",
             "EnviFormer",
             "ApplicabilityDomain",
+            "EnzymeLink",
         ]
         for model in MODELS:
             obj_cls = apps.get_model("epdb", model)

epdb/models.py

@@ -494,6 +494,20 @@ class ChemicalIdentifierMixin(ExternalIdentifierMixin):
         return self.get_external_identifier("CAS")
 
 
+class KEGGIdentifierMixin(ExternalIdentifierMixin):
+    @property
+    def kegg_reaction_links(self):
+        return self.get_external_identifier("KEGG Reaction")
+
+    def add_kegg_reaction_id(self, kegg_id):
+        return self.add_external_identifier(
+            "KEGG Reaction", kegg_id, f"https://www.genome.jp/entry/{kegg_id}"
+        )
+
+    class Meta:
+        abstract = True
+
+
 class ReactionIdentifierMixin(ExternalIdentifierMixin):
     class Meta:
         abstract = True
@@ -1014,6 +1028,26 @@ class CompoundStructure(EnviPathModel, AliasMixin, ScenarioMixin, ChemicalIdenti
         return self.compound.default_structure == self
 
 
+class EnzymeLink(EnviPathModel, KEGGIdentifierMixin):
+    rule = models.ForeignKey("Rule", on_delete=models.CASCADE, db_index=True)
+    ec_number = models.TextField(blank=False, null=False, verbose_name="EC Number")
+    classification_level = models.IntegerField(
+        blank=False, null=False, verbose_name="Classification Level"
+    )
+    linking_method = models.TextField(blank=False, null=False, verbose_name="Linking Method")
+
+    reaction_evidence = models.ManyToManyField("epdb.Reaction")
+    edge_evidence = models.ManyToManyField("epdb.Edge")
+
+    external_identifiers = GenericRelation("ExternalIdentifier")
+
+    def _url(self):
+        return "{}/enzymelink/{}".format(self.rule.url, self.uuid)
+
+    def get_group(self) -> str:
+        return ".".join(self.ec_number.split(".")[:3]) + ".-"
+
+
 class Rule(PolymorphicModel, EnviPathModel, AliasMixin, ScenarioMixin):
     package = models.ForeignKey(
         "epdb.Package", verbose_name="Package", on_delete=models.CASCADE, db_index=True
@@ -1095,6 +1129,18 @@ class Rule(PolymorphicModel, EnviPathModel, AliasMixin, ScenarioMixin):
 
         return new_rule
 
+    def enzymelinks(self):
+        return self.enzymelink_set.all()
+
+    def get_grouped_enzymelinks(self):
+        res = defaultdict(list)
+
+        for el in self.enzymelinks():
+            key = ".".join(el.ec_number.split(".")[:3]) + ".-"
+            res[key].append(el)
+
+        return dict(res)
+
 
 class SimpleRule(Rule):
     pass
@@ -1437,6 +1483,16 @@ class Reaction(EnviPathModel, AliasMixin, ScenarioMixin, ReactionIdentifierMixin
             id__in=Edge.objects.filter(edge_label=self).values("pathway_id")
         ).order_by("name")
 
+    def get_related_enzymes(self):
+        res = []
+        edges = Edge.objects.filter(edge_label=self)
+        for e in edges:
+            for scen in e.scenarios.all():
+                for ai in scen.additional_information.keys():
+                    if ai == "Enzyme":
+                        res.extend(scen.additional_information[ai])
+        return res
+
 
 class Pathway(EnviPathModel, AliasMixin, ScenarioMixin):
     package = models.ForeignKey(

epdb/urls.py

@@ -1,5 +1,5 @@
-from django.urls import path, re_path
 from django.contrib.auth import views as auth_views
+from django.urls import path, re_path
 
 from . import views as v
 
@@ -88,20 +88,36 @@ urlpatterns = [
         v.package_rule,
         name="package rule detail",
     ),
-    re_path(
+    # re_path(
-        rf"^package/(?P<package_uuid>{UUID})/simple-rdkit-rule/(?P<rule_uuid>{UUID})$",
+    #     rf"^package/(?P<package_uuid>{UUID})/simple-rdkit-rule/(?P<rule_uuid>{UUID})$",
-        v.package_rule,
+    #     v.package_rule,
-        name="package rule detail",
+    #     name="package rule detail",
-    ),
+    # ),
     re_path(
         rf"^package/(?P<package_uuid>{UUID})/parallel-rule/(?P<rule_uuid>{UUID})$",
         v.package_rule,
         name="package rule detail",
     ),
+    # re_path(
+    #     rf"^package/(?P<package_uuid>{UUID})/sequential-rule/(?P<rule_uuid>{UUID})$",
+    #     v.package_rule,
+    #     name="package rule detail",
+    # ),
+    # EnzymeLinks
     re_path(
-        rf"^package/(?P<package_uuid>{UUID})/sequential-rule/(?P<rule_uuid>{UUID})$",
+        rf"^package/(?P<package_uuid>{UUID})/rule/(?P<rule_uuid>{UUID})/enzymelink/(?P<enzymelink_uuid>{UUID})$",
-        v.package_rule,
+        v.package_rule_enzymelink,
-        name="package rule detail",
+        name="package rule enzymelink detail",
+    ),
+    re_path(
+        rf"^package/(?P<package_uuid>{UUID})/simple-ambit-rule/(?P<rule_uuid>{UUID})/enzymelink/(?P<enzymelink_uuid>{UUID})$",
+        v.package_rule_enzymelink,
+        name="package rule enzymelink detail",
+    ),
+    re_path(
+        rf"^package/(?P<package_uuid>{UUID})/parallel-rule/(?P<rule_uuid>{UUID})/enzymelink/(?P<enzymelink_uuid>{UUID})$",
+        v.package_rule_enzymelink,
+        name="package rule enzymelink detail",
     ),
     # Reaction
     re_path(

epdb/views.py

@@ -46,6 +46,7 @@ from .models import (
     Edge,
     ExternalDatabase,
     ExternalIdentifier,
+    EnzymeLink,
 )
 
 logger = logging.getLogger(__name__)
@@ -1528,6 +1529,32 @@ def package_rule(request, package_uuid, rule_uuid):
         return HttpResponseNotAllowed(["GET", "POST"])
 
 
+@package_permission_required()
+def package_rule_enzymelink(request, package_uuid, rule_uuid, enzymelink_uuid):
+    current_user = _anonymous_or_real(request)
+    current_package = PackageManager.get_package_by_id(current_user, package_uuid)
+    current_rule = Rule.objects.get(package=current_package, uuid=rule_uuid)
+    current_enzymelink = EnzymeLink.objects.get(rule=current_rule, uuid=enzymelink_uuid)
+
+    if request.method == "GET":
+        context = get_base_context(request)
+
+        context["title"] = f"enviPath - {current_package.name} - {current_rule.name}"
+
+        context["meta"]["current_package"] = current_package
+        context["object_type"] = "enzyme"
+        context["breadcrumbs"] = breadcrumbs(
+            current_package, "rule", current_rule, "enzymelink", current_enzymelink
+        )
+
+        context["enzymelink"] = current_enzymelink
+        context["current_object"] = current_enzymelink
+
+        return render(request, "objects/enzymelink.html", context)
+
+    return HttpResponseNotAllowed(["GET"])
+
+
 @package_permission_required()
 def package_reactions(request, package_uuid):
     current_user = _anonymous_or_real(request)

pyproject.toml

@@ -12,7 +12,6 @@ dependencies = [
     "django-ninja>=1.4.1",
     "django-oauth-toolkit>=3.0.1",
     "django-polymorphic>=4.1.0",
-    "django-stubs>=5.2.4",
     "enviformer",
     "envipy-additional-information",
     "envipy-ambit>=0.1.0",
@@ -33,12 +32,14 @@ dependencies = [
 [tool.uv.sources]
 enviformer = { git = "ssh://git@git.envipath.com/enviPath/enviformer.git", rev = "v0.1.2" }
 envipy-plugins = { git = "ssh://git@git.envipath.com/enviPath/enviPy-plugins.git", rev = "v0.1.0" }
-envipy-additional-information = { git = "ssh://git@git.envipath.com/enviPath/enviPy-additional-information.git", rev = "v0.1.4"}
+envipy-additional-information = { git = "ssh://git@git.envipath.com/enviPath/enviPy-additional-information.git", rev = "v0.1.7"}
 envipy-ambit = { git = "ssh://git@git.envipath.com/enviPath/enviPy-ambit.git" }
 
 [project.optional-dependencies]
 ms-login = ["msal>=1.33.0"]
 dev = [
+    "celery-stubs==0.1.3",
+    "django-stubs>=5.2.4",
     "poethepoet>=0.37.0",
     "pre-commit>=4.3.0",
     "ruff>=0.13.3",

templates/objects/composite_rule.html

@@ -29,7 +29,7 @@
         </div>
         <div class="panel-body">
             <p>
-                {{ rule.description }}
+                {{ rule.description|safe }}
             </p>
         </div>
 
@@ -87,6 +87,7 @@
             </div>
         {% endif %}
 
+        {% if rule.enzymelinks %}
             <!-- EC Numbers -->
             <div class="panel panel-default panel-heading list-group-item" style="background-color:silver">
                 <h4 class="panel-title">
@@ -94,12 +95,33 @@
                        href="#rule-ec-numbers">EC Numbers</a>
                 </h4>
             </div>
-        <div id="rule-ec-numbers" class="panel-collapse collapse">
+            <div id="rule-ec-numbers" class="panel-collapse collapse in">
                 <div class="panel-body list-group-item">
-
+                    {% for k, v in rule.get_grouped_enzymelinks.items %}
+                        <div class="panel panel-default panel-heading list-group-item" style="background-color:silver">
+                            <h4 class="panel-title">
+                                <a id="{{ k|slugify }}_Link" data-toggle="collapse"
+                                   data-parent="#{{ k|slugify }}_Accordion"
+                                   href="#{{ k|slugify }}">
+                                    {{ k }}
+                                </a>
+                            </h4>
+                        </div>
+                        <div id="{{ k|slugify }}" class="panel-collapse collapse in">
+                            <div class="panel-body list-group-item">
+                                {% for enzyme in v %}
+                                    <a class="list-group-item" href="{{ enzyme.url }}">
+                                        {{ enzyme.ec_number }}
+                                        <div style="position:absolute;bottom:10px;left:100px;">{{ enzyme.name }}</div>
+                                        <div style="float:right;">{{ enzyme.linking_method }}</div>
+                                    </a>
+                                {% endfor %}
                             </div>
                         </div>
-
+                    {% endfor %}
+                </div>
+            </div>
+        {% endif %}
     </div>
 </div>
 {% endblock content %}

templates/objects/enzymelink.html

@@ -0,0 +1,105 @@
+{% extends "framework.html" %}
+
+{% block content %}
+
+    <div class="panel-group" id="enzyme-detail">
+        <div class="panel panel-default">
+            <div class="panel-heading" id="headingPanel" style="font-size:2rem;height: 46px">
+                {{ enzymelink.ec_number }}
+            </div>
+
+            <!-- Name -->
+            <div class="panel panel-default panel-heading list-group-item" style="background-color:silver">
+                <h4 class="panel-title">
+                    <a id="enzyme-name-link" data-toggle="collapse" data-parent="#enzyme-detail"
+                       href="#enzyme-name">Enzyme Name</a>
+                </h4>
+            </div>
+            <div id="enzyme-name" class="panel-collapse collapse in">
+                <div class="panel-body list-group-item">
+                    {{ enzymelink.name }}
+                </div>
+            </div>
+
+            <!-- Linking Method -->
+            <div class="panel panel-default panel-heading list-group-item" style="background-color:silver">
+                <h4 class="panel-title">
+                    <a id="enzyme-linking-link" data-toggle="collapse" data-parent="#enzyme-detail"
+                       href="#enzyme-linking">Linking Method</a>
+                </h4>
+            </div>
+            <div id="enzyme-linking" class="panel-collapse collapse in">
+                <div class="panel-body list-group-item">
+                    {{ enzymelink.linking_method }}. &nbsp;<a
+                        href="https://wiki.envipath.org/index.php/Rules#EnzymeLinks" target="#">Learn more &gt;&gt;</a>
+                </div>
+            </div>
+
+            {% if enzymelink.kegg_reaction_links %}
+                <div class="panel panel-default panel-heading list-group-item" style="background-color:silver">
+                    <h4 class="panel-title">
+                        <a id="enzyme-evidence-link" data-toggle="collapse" data-parent="#enzyme-detail"
+                           href="#enzyme-evidence">Linking Evidence</a>
+                    </h4>
+                </div>
+                <div id="enzyme-evidence" class="panel-collapse collapse in">
+                    <div class="panel-body list-group-item">
+                        {% for kl in enzymelink.kegg_reaction_links %}
+                            <a class="list-group-item"
+                               href="{{ kl.external_url }}">{{ kl.identifier_value }}</a>
+                        {% endfor %}
+                    </div>
+                </div>
+            {% endif %}
+
+            {% if enzymelink.reaction_evidence.all %}
+                <div class="panel panel-default panel-heading list-group-item" style="background-color:silver">
+                    <h4 class="panel-title">
+                        <a id="enzyme-reaction-evidence-link" data-toggle="collapse" data-parent="#enzyme-detail"
+                           href="#enzyme-reaction-evidence">Linking Evidence - enviPath Reactions</a>
+                    </h4>
+                </div>
+                <div id="enzyme-reaction-evidence" class="panel-collapse collapse in">
+                    <div class="panel-body list-group-item">
+                        {% for r in enzymelink.reaction_evidence.all %}
+                            <a class="list-group-item" href="{{ r.url }}">{{ r.name }} <i>({{ r.package.name }})</i></a>
+                        {% endfor %}
+                    </div>
+                </div>
+            {% endif %}
+
+            {% if enzymelink.edge_evidence.all %}
+                <div class="panel panel-default panel-heading list-group-item" style="background-color:silver">
+                    <h4 class="panel-title">
+                        <a id="enzyme-edge-evidence-link" data-toggle="collapse" data-parent="#enzyme-detail"
+                           href="#enzyme-edge-evidence">Linking Evidence - enviPath Pathways</a>
+                    </h4>
+                </div>
+                <div id="enzyme-edge-evidence" class="panel-collapse collapse in">
+                    <div class="panel-body list-group-item">
+                        {% for e in enzymelink.edge_evidence.all %}
+                            <a class="list-group-item" href="{{ e.pathway.url }}">{{ e.pathway.name }}
+                                <i>({{ r.package.name }})</i></a>
+                        {% endfor %}
+                    </div>
+                </div>
+            {% endif %}
+
+            <!-- External DB Reference -->
+            <div class="panel panel-default panel-heading list-group-item" style="background-color:silver">
+                <h4 class="panel-title">
+                    <a id="enzyme-external-identifier-link" data-toggle="collapse" data-parent="#enzyme-detail"
+                       href="#enzyme-external-identifier">External DB References</a>
+                </h4>
+            </div>
+            <div id="enzyme-external-identifier" class="panel-collapse collapse in">
+                <div class="panel-body list-group-item">
+                    <a class="list-group-item"
+                       href="http://www.brenda-enzymes.org/enzyme.php?ecno={{ enzymelink.ec_number }}"
+                       target="_blank"> Brenda entry for {{ enzymelink.ec_number }}</a>
+                </div>
+            </div>
+
+        </div>
+    </div>
+{% endblock content %}

templates/objects/reaction.html

@@ -124,6 +124,23 @@
                 </div>
             {% endif %}
 
+            {% if reaction.get_related_enzymes %}
+                <!-- EC Numbers -->
+                <div class="panel panel-default panel-heading list-group-item" style="background-color:silver">
+                    <h4 class="panel-title">
+                        <a id="rule-ec-numbers-link" data-toggle="collapse" data-parent="#rule-detail"
+                           href="#rule-ec-numbers">EC Numbers</a>
+                    </h4>
+                </div>
+                <div id="rule-ec-numbers" class="panel-collapse collapse in">
+                    <div class="panel-body list-group-item">
+                        {% for e in reaction.get_related_enzymes %}
+                            <a class="list-group-item" href="http://www.brenda-enzymes.org/enzyme.php?ecno={{ e.ec_number }}">{{ e.name }}</a>
+                        {% endfor %}
+                    </div>
+                </div>
+            {% endif %}
+
             {% if reaction.related_pathways %}
                 <!-- Pathways -->
                 <div class="panel panel-default panel-heading list-group-item" style="background-color:silver">

templates/objects/simple_rule.html

@@ -201,6 +201,43 @@
                     </div>
                 </div>
             {% endif %}
+
+            {% if rule.enzymelinks %}
+                <!-- EC Numbers -->
+                <div class="panel panel-default panel-heading list-group-item" style="background-color:silver">
+                    <h4 class="panel-title">
+                        <a id="rule-ec-numbers-link" data-toggle="collapse" data-parent="#rule-detail"
+                           href="#rule-ec-numbers">EC Numbers</a>
+                    </h4>
+                </div>
+                <div id="rule-ec-numbers" class="panel-collapse collapse in">
+                    <div class="panel-body list-group-item">
+                        {% for k, v in rule.get_grouped_enzymelinks.items %}
+                            <div class="panel panel-default panel-heading list-group-item"
+                                 style="background-color:silver">
+                                <h4 class="panel-title">
+                                    <a id="{{ k|slugify }}_Link" data-toggle="collapse"
+                                       data-parent="#{{ k|slugify }}_Accordion"
+                                       href="#{{ k|slugify }}">
+                                        {{ k }}
+                                    </a>
+                                </h4>
+                            </div>
+                            <div id="{{ k|slugify }}" class="panel-collapse collapse in">
+                                <div class="panel-body list-group-item">
+                                    {% for enzyme in v %}
+                                        <a class="list-group-item" href="{{ enzyme.url }}">
+                                            {{ enzyme.ec_number }}
+                                            <div style="position:absolute;bottom:10px;left:100px;">{{ enzyme.name }}</div>
+                                            <div style="float:right;">{{ enzyme.linking_method }}</div>
+                                        </a>
+                                    {% endfor %}
+                                </div>
+                            </div>
+                        {% endfor %}
+                    </div>
+                </div>
+            {% endif %}
         </div>
     </div>
 {% endblock content %}