This is version 1.0 of the BioPAX Level 2 ontology. The goal of the BioPAX group is to develop a common exchange format for biological pathway data. More information is available at http://www.biopax.org. This ontology is freely available under the LGPL (http://www.gnu.org/copyleft/lesser.html). Definition: The direct source of this data. This does not store the trail of sources from the generation of the data to this point, only the last known source, such as a database. The XREF property may contain a publicationXref referencing a publication describing the data source (e.g. a database publication). A unificationXref may be used e.g. when pointing to an entry in a database of databases describing this database. Examples: A database or person name. Definition: Used to import terms from external controlled vocabularies (CVs) into the ontology. To support consistency and compatibility, open, freely available CVs should be used whenever possible, such as the Gene Ontology (GO) or other open biological CVs listed on the OBO website (http://obo.sourceforge.net/). Comment: The ID property in unification xrefs to GO and other OBO ontologies should include the ontology name in the ID property (e.g. ID="GO:0005634" instead of ID="0005634"). Definition: A DNA, RNA or protein participant in an interaction. Comment: See physicalEntityParticipant for more documentation. Definition: A conversion interaction that is both a biochemicalReaction and a transport. In transportWithBiochemicalReaction interactions, one or more of the substrates change both their location and their physical structure. Active transport reactions that use ATP as an energy source fall under this category, even if the only covalent change is the hydrolysis of ATP to ADP. Comment: This class was added to support a large number of transport events in pathway databases that have a biochemical reaction during the transport process. It is not expected that other double inheritance subclasses will be added to the ontology at the same level as this class. Examples: In the PEP-dependent phosphotransferase system, transportation of sugar into an E. coli cell is accompanied by the sugar's phosphorylation as it crosses the plasma membrane. Definition: A conversion interaction in which a set of physical entities, at least one being a macromolecule (e.g. protein, RNA, DNA), aggregate via non-covalent interactions. One of the participants of a complexAssembly must be an instance of the class complex (via a physicalEntityParticipant instance). Comment: This class is also used to represent complex disassembly. The assembly or disassembly of a complex is often a spontaneous process, in which case the direction of the complexAssembly (toward either assembly or disassembly) should be specified via the SPONTANEOUS property. Synonyms: aggregation, complex formation Examples: Assembly of the TFB2 and TFB3 proteins into the TFIIH complex, and assembly of the ribosome through aggregation of its subunits. Note: The following are not examples of complex assembly: Covalent phosphorylation of a protein (this is a biochemicalReaction); the TFIIH complex itself (this is an instance of the complex class, not the complexAssembly class). Definition: An entity with a physical structure. A pool of entities, not a specific molecular instance of an entity in a cell. Comment: This class serves as the super-class for all physical entities, although its current set of subclasses is limited to molecules. As a highly abstract class in the ontology, instances of the physicalEntity class should never be created. Instead, more specific classes should be used. Synonyms: part, interactor, object Naming rationale: It's difficult to find a name that encompasses all of the subclasses of this class without being too general. E.g. PSI-MI uses 'interactor', BIND uses 'object', BioCyc uses 'chemicals'. physicalEntity seems to be a good name for this specialization of entity. Examples: protein, small molecule, RNA 1 Definition: A unification xref defines a reference to an entity in an external resource that has the same biological identity as the referring entity. For example, if one wished to link from a database record, C, describing a chemical compound in a BioPAX data collection to a record, C', describing the same chemical compound in an external database, one would use a unification xref since records C and C' describe the same biological identity. Generally, unification xrefs should be used whenever possible, although there are cases where they might not be useful, such as application to application data exchange. Comment: Unification xrefs in physical entities are essential for data integration, but are less important in interactions. This is because unification xrefs on the physical entities in an interaction can be used to compute the equivalence of two interactions of the same type. An xref in a protein pointing to a gene, e.g. in the LocusLink database17, would not be a unification xref since the two entities do not have the same biological identity (one is a protein, the other is a gene). Instead, this link should be a captured as a relationship xref. References to an external controlled vocabulary term within the OpenControlledVocabulary class should use a unification xref where possible (e.g. GO:0005737). Examples: An xref in a protein instance pointing to an entry in the Swiss-Prot database, and an xref in an RNA instance pointing to the corresponding RNA sequence in the RefSeq database.. 1 1 1 1 Definition: An xref that defines a reference to an entity in an external resource that does not have the same biological identity as the referring entity. Comment: There is currently no controlled vocabulary of relationship types for BioPAX, although one will be created in the future if a need develops. Examples: A link between a gene G in a BioPAX data collection, and the protein product P of that gene in an external database. This is not a unification xref because G and P are different biological entities (one is a gene and one is a protein). Another example is a relationship xref for a protein that refers to the Gene Ontology biological process, e.g. 'immune response,' that the protein is involved in. Definition: An interaction in which at least one participant is a physical entity, e.g. a binding event. Comment: This class should be used by default for representing molecular interactions, such as those defined by PSI-MI level 2. The participants in a molecular interaction should be listed in the PARTICIPANTS slot. Note that this is one of the few cases in which the PARTICPANT slot should be directly populated with instances (see comments on the PARTICPANTS property in the interaction class description). If sufficient information on the nature of a molecular interaction is available, a more specific BioPAX interaction class should be used. Example: Two proteins observed to interact in a yeast-two-hybrid experiment where there is not enough experimental evidence to suggest that the proteins are forming a complex by themselves without any indirect involvement of other proteins. This is the case for most large-scale yeast two-hybrid screens. 1 Definition: Any bioactive molecule that is not a peptide, DNA, or RNA. Generally these are non-polymeric, but complex carbohydrates are not explicitly modeled as classes in this version of the ontology, thus are forced into this class. Comment: Recently, a number of small molecule databases have become available to cross-reference from this class. Examples: glucose, penicillin, phosphatidylinositol 1 Definition: A location on a nucleotide or amino acid sequence. Comment: For organizational purposes only; direct instances of this class should not be created. 1 1 Definition: Describes an interval on a sequence. All of the sequence from the begin site to the end site (inclusive) is described, not any subset. Definition: A conversion interaction in which an entity (or set of entities) changes location within or with respect to the cell. A transport interaction does not include the transporter entity, even if one is required in order for the transport to occur. Instead, transporters are linked to transport interactions via the catalysis class. Comment: Transport interactions do not involve chemical changes of the participant(s). These cases are handled by the transportWithBiochemicalReaction class. Synonyms: translocation. Examples: The movement of Na+ into the cell through an open voltage-gated channel. Definition: Describes a site on a sequence, i.e. the position of a single nucleotide or amino acid. 1 1 Definition: A conversion interaction in which one or more entities (substrates) undergo covalent changes to become one or more other entities (products). The substrates of biochemical reactions are defined in terms of sums of species. This is convention in biochemistry, and, in principle, all of the EC reactions should be biochemical reactions. Examples: ATP + H2O = ADP + Pi Comment: In the example reaction above, ATP is considered to be an equilibrium mixture of several species, namely ATP4-, HATP3-, H2ATP2-, MgATP2-, MgHATP-, and Mg2ATP. Additional species may also need to be considered if other ions (e.g. Ca2+) that bind ATP are present. Similar considerations apply to ADP and to inorganic phosphate (Pi). When writing biochemical reactions, it is not necessary to attach charges to the biochemical reactants or to include ions such as H+ and Mg2+ in the equation. The reaction is written in the direction specified by the EC nomenclature system, if applicable, regardless of the physiological direction(s) in which the reaction proceeds. Polymerization reactions involving large polymers whose structure is not explicitly captured should generally be represented as unbalanced reactions in which the monomer is consumed but the polymer remains unchanged, e.g. glycogen + glucose = glycogen. Definition: A physical entity whose structure is comprised of other physical entities bound to each other non-covalently, at least one of which is a macromolecule (e.g. protein, DNA, or RNA). Complexes must be stable enough to function as a biological unit; in general, the temporary association of an enzyme with its substrate(s) should not be considered or represented as a complex. A complex is the physical product of an interaction (complexAssembly) and is not itself considered an interaction. Comment: In general, complexes should not be defined recursively so that smaller complexes exist within larger complexes, i.e. a complex should not be a COMPONENT of another complex (see comments on the COMPONENT property). The boundaries on the size of complexes described by this class are not defined here, although elements of the cell as large and dynamic as, e.g., a mitochondrion would typically not be described using this class (later versions of this ontology may include a cellularComponent class to represent these). The strength of binding and the topology of the components cannot be described currently, but may be included in future versions of the ontology, depending on community need. Examples: Ribosome, RNA polymerase II. Other examples of this class include complexes of multiple protein monomers and complexes of proteins and small molecules. 1 1 Definition: An xref that defines a reference to a publication such as a book, journal article, web page, or software manual. The reference may or may not be in a database, although references to PubMed are preferred when possible. The publication should make a direct reference to the instance it is attached to. Comment: Publication xrefs should make use of PubMed IDs wherever possible. The DB property of an xref to an entry in PubMed should use the string "PubMed" and not "MEDLINE". Examples: PubMed:10234245 1 Definition: A feature on a sequence relevant to an interaction, such as a binding site or post-translational modification. Examples: A phosphorylation on a protein. 1 1 1 1 Definition: A discrete biological unit used when describing pathways. Comment: This is the root class for all biological concepts in the ontology, which include pathways, interactions and physical entities. As the most abstract class in the ontology, instances of the entity class should never be created. Instead, more specific classes should be used. Synonyms: thing, object, bioentity. Definition: Confidence that the containing instance actually occurs or exists in vivo, usually a statistical measure. The xref must contain at least on publication that describes the method used to determine the confidence. There is currently no standard way of describing confidence values, so any string is valid for the confidence value. In the future, a controlled vocabulary of accepted confidence values could become available, in which case it will likely be adopted for use here to describe the value. Examples: The statistical significance of a result, e.g. "p<0.05". 1 1 1 Definition: A step in a pathway. Comment: Multiple interactions may occur in a pathway step, each should be listed in the STEP-INTERACTIONS property. Order relationships between pathway steps may be established with the NEXT-STEP slot. This order may not be temporally meaningful for specific steps, such as for a pathway loop or a reversible reaction, but represents a directed graph of step relationships that can be useful for describing the overall flow of a pathway, as may be useful in a pathway diagram. Example: A metabolic pathway may contain a pathway step composed of one biochemical reaction (BR1) and one catalysis (CAT1) instance, where CAT1 describes the catalysis of BR1. Definition: Utility classes are created when simple slots are insufficient to describe an aspect of an entity or to increase compatibility of this ontology with other standards. The utilityClass class is actually a metaclass and is only present to organize the other helper classes under one class hierarchy; instances of utilityClass should never be created. Definition: A set or series of interactions, often forming a network, which biologists have found useful to group together for organizational, historic, biophysical or other reasons. Comment: It is possible to define a pathway without specifying the interactions within the pathway. In this case, the pathway instance could consist simply of a name and could be treated as a 'black box'. Synonyms: network Examples: glycolysis, valine biosynthesis 1 Definition: A pointer to an external object, such as an entry in a database or a term in a controlled vocabulary. Comment: This class is for organizational purposes only; direct instances of this class should not be created. Definition: A physical entity consisting of a sequence of deoxyribonucleotide monophosphates; a deoxyribonucleic acid. Comment: This is not a 'gene', since gene is a genetic concept, not a physical entity. The concept of a gene may be added later in BioPAX. Examples: a chromosome, a plasmid. A specific example is chromosome 7 of Homo sapiens. 1 Definition: A control interaction in which a physical entity modulates a catalysis interaction. Biologically, most modulation interactions describe an interaction in which a small molecule alters the ability of an enzyme to catalyze a specific reaction. Instances of this class describe a pairing between a modulating entity and a catalysis interaction. Comment: A separate modulation instance should be created for each different catalysis instance that a physical entity may modulate and for each different physical entity that may modulate a catalysis instance. A typical modulation instance has a small molecule as the controller entity and a catalysis instance as the controlled entity. Examples: Allosteric activation and competitive inhibition of an enzyme's ability to catalyze a specific reaction. 1 1 Definition: A physical entity consisting of a sequence of amino acids; a protein monomer; a single polypeptide chain. Examples: The epidermal growth factor receptor (EGFR) protein. 1 1 1 1 Definition: A reference from an instance of a class in this ontology to an object in an external resource. Comment: Instances of the xref class should never be created and more specific classes should be used instead. 1 Definition: The form of a physical entity in a particular experiment, as it may be modified for purposes of experimental design. Examples: A His-tagged protein in a binding assay. A protein can be tagged by multiple tags, so can have more than 1 experimental form type terms 1 1 1 1 Definition: A physical entity consisting of a sequence of ribonucleotide monophosphates; a ribonucleic acid. Examples: messengerRNA, microRNA, ribosomalRNA. A specific example is the let-7 microRNA. 1 Definition: An interaction in which one entity regulates, modifies, or otherwise influences another. Two types of control interactions are defined: activation and inhibition. Comment: In general, the targets of control processes (i.e. occupants of the CONTROLLED property) should be interactions. Conceptually, physical entities are involved in interactions (or events) and the events should be controlled or modified, not the physical entities themselves. For example, a kinase activating a protein is a frequent event in signaling pathways and is usually represented as an 'activation' arrow from the kinase to the substrate in signaling diagrams. This is an abstraction that can be ambiguous out of context. In BioPAX, this information should be captured as the kinase catalyzing (via an instance of the catalysis class) a reaction in which the substrate is phosphorylated, instead of as a control interaction in which the kinase activates the substrate. Since this class is a superclass for specific types of control, instances of the control class should only be created when none of its subclasses are applicable. Synonyms: regulation, mediation Examples: A small molecule that inhibits a pathway by an unknown mechanism controls the pathway. 1 1 Definition: The apparent equilibrium constant, K', and associated values. Concentrations in the equilibrium constant equation refer to the total concentrations of all forms of particular biochemical reactants. For example, in the equilibrium constant equation for the biochemical reaction in which ATP is hydrolyzed to ADP and inorganic phosphate: K' = [ADP][P_i]/[ATP], The concentration of ATP refers to the total concentration of all of the following species: [ATP] = [ATP^4-] + [HATP^3-] + [H₂ATP^2-] + [MgATP^2-] + [MgHATP^-] + [Mg₂ATP]. The apparent equilibrium constant is formally dimensionless, and can be kept so by inclusion of as many of the terms (1 mol/dm³) in the numerator or denominator as necessary. It is a function of temperature (T), ionic strength (I), pH, and pMg (pMg = -log₁₀[Mg²⁺]). Therefore, these quantities must be specified to be precise, and values for KEQ for biochemical reactions may be represented as 5-tuples of the form (K' T I pH pMg). This property may have multiple values, representing different measurements for K' obtained under the different experimental conditions listed in the 5-tuple. (This definition adapted from EcoCyc) See http://www.chem.qmul.ac.uk/iubmb/thermod/ for a thermodynamics tutorial. 1 1 1 Definition: Any additional special characteristics of a physical entity in the context of an interaction or complex. These currently include stoichiometric coefficient and cellular location, but this list may be expanded in later levels. Comment: PhysicalEntityParticipants should not be used in multiple interaction or complex instances. Instead, each interaction and complex should reference its own unique set of physicalEntityParticipants. The reason for this is that a user may add new information about a physicalEntityParticipant for one interaction or complex, such as the presence of a previously unknown post-translational modification, and unwittingly invalidate the physicalEntityParticipant for the other interactions or complexes that make use of it. Example: In the interaction describing the transport of L-arginine into the cytoplasm in E. coli, the LEFT property in the interaction would be filled with an instance of physicalEntityParticipant that specified the location of L-arginine as periplasm and the stoichiometric coefficient as one. 1 1 1 Definition: A single biological relationship between two or more entities. An interaction cannot be defined without the entities it relates. Comment: Since it is a highly abstract class in the ontology, instances of the interaction class should never be created. Instead, more specific classes should be used. Currently this class only has subclasses that define physical interactions; later levels of BioPAX may define other types of interactions, such as genetic (e.g. synthetic lethal). Naming rationale: A number of names were considered for this concept, including "process", "synthesis" and "relationship"; Interaction was chosen as it is understood by biologists in a biological context and is compatible with PSI-MI. Examples: protein-protein interaction, biochemical reaction, enzyme catalysis 1 1 1 1 1 Definition: For biochemical reactions, this property refers to the standard transformed Gibbs energy change for a reaction written in terms of biochemical reactants (sums of species), delta-G'^o. delta-G'^o = -RT lnK' and delta-G'^o = delta-H'^o - T delta-S'^o delta-G'^o has units of kJ/mol. Like K', it is a function of temperature (T), ionic strength (I), pH, and pMg (pMg = -log₁₀[Mg²⁺]). Therefore, these quantities must be specified, and values for DELTA-G for biochemical reactions are represented as 5-tuples of the form (delta-G'^o T I pH pMg). This property may have multiple values, representing different measurements for delta-G'^o obtained under the different experimental conditions listed in the 5-tuple. (This definition from EcoCyc) ACTIVATION 1 1 Definition: A control interaction in which a physical entity (a catalyst) increases the rate of a conversion interaction by lowering its activation energy. Instances of this class describe a pairing between a catalyzing entity and a catalyzed conversion. Comment: A separate catalysis instance should be created for each different conversion that a physicalEntity may catalyze and for each different physicalEntity that may catalyze a conversion. For example, a bifunctional enzyme that catalyzes two different biochemical reactions would be linked to each of those biochemical reactions by two separate instances of the catalysis class. Also, catalysis reactions from multiple different organisms could be linked to the same generic biochemical reaction (a biochemical reaction is generic if it only includes small molecules). Generally, the enzyme catalyzing a conversion is known and the use of this class is obvious. In the cases where a catalyzed reaction is known to occur but the enzyme is not known, a catalysis instance should be created without a controller specified (i.e. the CONTROLLER property should remain empty). Synonyms: facilitation, acceleration. Examples: The catalysis of a biochemical reaction by an enzyme, the enabling of a transport interaction by a membrane pore complex, and the facilitation of a complex assembly by a scaffold protein. Hexokinase -> (The "Glucose + ATP -> Glucose-6-phosphate +ADP" reaction). A plasma membrane Na+/K+ ATPase is an active transporter (antiport pump) using the energy of ATP to pump Na+ out of the cell and K+ in. Na+ from cytoplasm to extracellular space would be described in a transport instance. K+ from extracellular space to cytoplasm would be described in a transport instance. The ATPase pump would be stored in a catalysis instance controlling each of the above transport instances. A biochemical reaction that does not occur by itself under physiological conditions, but has been observed to occur in the presence of cell extract, likely via one or more unknown enzymes present in the extract, would be stored in the CONTROLLED property, with the CONTROLLER property empty. 1 Definition: The support for a particular assertion, such as the existence of an interaction or pathway. At least one of CONFIDENCE, EVIDENCE-CODE, or EXPERIMENTAL-FORM must be instantiated when creating an evidence instance. XREF may reference a publication describing the experimental evidence using a publicationXref or may store a description of the experiment in an experimental description database using a unificationXref (if the referenced experiment is the same) or relationshipXref (if it is not identical, but similar in some way e.g. similar in protocol). Evidence is meant to provide more information than just an xref to the source paper. Examples: A description of a molecular binding assay that was used to detect a protein-protein interaction. 1 1 1 1 Definition: An interaction in which one or more entities is physically transformed into one or more other entities. Comment: This class is designed to represent a simple, single-step transformation. Multi-step transformations, such as the conversion of glucose to pyruvate in the glycolysis pathway, should be represented as pathways, if known. Since it is a highly abstract class in the ontology, instances of the conversion class should never be created. Examples: A biochemical reaction converts substrates to products, the process of complex assembly converts single molecules to a complex, transport converts entities in one compartment to the same entities in another compartment. 1 1 1 Definition: The biological source of an entity (e.g. protein, RNA or DNA). Some entities are considered source-neutral (e.g. small molecules), and the biological source of others can be deduced from their constituentss (e.g. complex, pathway). Examples: HeLa cells, human, and mouse liver tissue. 1 1 Definition: Describes a small molecule structure. Structure information is stored in the property STRUCTURE-DATA, in one of three formats: the CML format (see URL www.xml-cml.org), the SMILES format (see URL www.daylight.com/dayhtml/smiles/) or the InChI format (http://www.iupac.org/inchi/). The STRUCTURE-FORMAT property specifies which format is used. Comment: By virtue of the expressivity of CML, an instance of this class can also provide additional information about a small molecule, such as its chemical formula, names, and synonyms, if CML is used as the structure format. Examples: The following SMILES string, which describes the structure of glucose-6-phosphate: 'C(OP(=O)(O)O)[CH]1([CH](O)[CH](O)[CH](O)[CH](O)O1)'. 1 The controlling entity, e.g., in a biochemical reaction, an enzyme is the controlling entity of the reaction. CONTROLLER is a sub-property of PARTICIPANTS. This property lists the entities that participate in this interaction. For example, in a biochemical reaction, the participants are the union of the reactants and the products of the reaction. This property has a number of sub-properties, such as LEFT and RIGHT in the biochemicalInteraction class. Any participant listed in a sub-property will automatically be assumed to also be in PARTICIPANTS by a number of software systems, including Prot??g??, so this property should not contain any instances if there are instances contained in a sub-property. Values of this property define external cross-references from this entity to entities in external databases. Description and classification of the feature. The set of interactions and/or pathwaySteps in this pathway/network. Each instance of the pathwayStep class defines: 1) a set of interactions that together define a particular step in the pathway, for example a catalysis instance and the conversion that it catalyzes; 2) an order relationship to one or more other pathway steps (via the NEXT-STEP property). Note: This ordering is not necessarily temporal - the order described may simply represent connectivity between adjacent steps. Temporal ordering information should only be inferred from the direction of each interaction. The participant that has the experimental form being described. The physical entity annotated with stoichiometry and cellular location attributes from the physicalEntityParticipant instance. Scientific evidence supporting the existence of the entity as described. The participants on the right side of the conversion interaction. Since conversion interactions may proceed in either the left-to-right or right-to-left direction, occupants of the RIGHT property may be either reactants or products. RIGHT is a sub-property of PARTICIPANTS. The begin position of a sequence interval. The interactions that take place at this step of the pathway. External controlled vocabulary characterizing the interaction type, for example "phosphorylation". Confidence in the containing instance. Usually a statistical measure. A pointer to a term in an external controlled vocabulary, such as the GO, PSI-MI or BioCyc evidence codes, that describes the nature of the support, such as 'traceable author statement' or 'yeast two-hybrid'. An organism, e.g. 'Homo sapiens'. This is the organism that the entity is found in. Pathways may not have an organism associated with them, for instance, reference pathways from KEGG. Sequence-based entities (DNA, protein, RNA) may contain an xref to a sequence database that contains organism information, in which case the information should be consistent with the value for ORGANISM. For biochemical reactions, this property refers to the standard transformed Gibbs energy change for a reaction written in terms of biochemical reactants (sums of species), delta-G'^o. delta-G'^o = -RT lnK' and delta-G'^o = delta-H'^o - T delta-S'^o delta-G'^o has units of kJ/mol. Like K', it is a function of temperature (T), ionic strength (I), pH, and pMg (pMg = -log₁₀[Mg²⁺]). Therefore, these quantities must be specified, and values for DELTA-G for biochemical reactions are represented as 5-tuples of the form (delta-G'^o T I pH pMg). This property may have multiple values, representing different measurements for delta-G'^o obtained under the different experimental conditions listed in the 5-tuple. (This definition from EcoCyc) Defines the chemical structure and other information about this molecule, using an instance of class chemicalStructure. Sequence features relevant for the interaction, for example binding domains or modification sites. Warning: this property may be moved into a state class in Level 3. An xref to an organism taxonomy database, preferably NCBI taxon. This should be an instance of unificationXref, unless the organism is not in an existing database. The participants on the left side of the conversion interaction. Since conversion interactions may proceed in either the left-to-right or right-to-left direction, occupants of the LEFT property may be either reactants or products. LEFT is a sub-property of PARTICIPANTS. The entity that is controlled, e.g., in a biochemical reaction, the reaction is controlled by an enzyme. CONTROLLED is a sub-property of PARTICIPANTS. An external controlled vocabulary of tissue types. Defines the physicalEntity subunits of this complex. This property should not contain other complexes, i.e. it should always be a flat representation of the complex. For example, if two protein complexes join to form a single larger complex via a complex assembly interaction, the COMPONENTS of the new complex should be the individual proteins of the smaller complexes, not the two smaller complexes themselves. Exceptions are black-box complexes (i.e. complexes in which the COMPONENTS property is empty), which may be used as COMPONENTS of other complexes (via a physicalEntityParticipant instance) because their constituent parts are unknown / unspecified. The reason for keeping complexes flat is to signify that there is no information stored in the way complexes are nested, such as assembly order. Any cofactor(s) or coenzyme(s) required for catalysis of the conversion by the enzyme. COFACTOR is a sub-property of PARTICIPANTS. A cellular location, e.g. 'cytoplasm'. This should reference a term in the Gene Ontology Cellular Component ontology. The location referred to by this property should be as specific as is known. If an interaction is known to occur in multiple locations, separate interactions (and physicalEntityParticipants) must be created for each different location. Note: If a location is unknown then the GO term for 'cellular component unknown' (GO:0008372) should be used in the LOCATION property. If the location of a participant in a complex is unspecified, it may be assumed to be the same location as that of the complex. In case of conflicting information, the location of the most outer layer of any nesting should be considered correct. Note: Cellular location describes a specific location of a physical entity as it would be used in e.g. a transport reaction. It does not describe all of the possible locations that the physical entity could be in the cell. The next step(s) of the pathway. Contains zero or more pathwayStep instances. If there is no next step, this property is empty. Location of the feature on the sequence of the interactor. One feature may have more than one location, used e.g. for features which involve sequence positions close in the folded, three-dimensional state of a protein, but non-continuous along the sequence. The experimental forms associated with an evidence instance. The end position of a sequence interval. Descriptor of this experimental form from a controlled vocabulary. This quantity is dimensionless and is usually a single number. The measured equilibrium constant for a biochemical reaction, encoded by the slot KEQ, is actually the apparent equilibrium constant, K'. Concentrations in the equilibrium constant equation refer to the total concentrations of all forms of particular biochemical reactants. For example, in the equilibrium constant equation for the biochemical reaction in which ATP is hydrolyzed to ADP and inorganic phosphate: K' = [ADP][P_i]/[ATP], The concentration of ATP refers to the total concentration of all of the following species: [ATP] = [ATP^4-] + [HATP^3-] + [H₂ATP^2-] + [MgATP^2-] + [MgHATP^-] + [Mg₂ATP]. The apparent equilibrium constant is formally dimensionless, and can be kept so by inclusion of as many of the terms (1 mol/dm³) in the numerator or denominator as necessary. It is a function of temperature (T), ionic strength (I), pH, and pMg (pMg = -log₁₀[Mg²⁺]). Therefore, these quantities must be specified to be precise, and values for KEQ for biochemical reactions may be represented as 5-tuples of the form (K' T I pH pMg). This property may have multiple values, representing different measurements for K' obtained under the different experimental conditions listed in the 5-tuple. (This definition adapted from EcoCyc) A free text description of the source of this data, e.g. a database or person name. This property should be used to describe the source of the data. This is meant to be used by databases that export their data to the BioPAX format or by systems that are integrating data from multiple sources. The granularity of use (specifying the data source in many or few instances) is up to the user. It is intended that this property report the last data source, not all data sources that the data has passed through from creation. A cell type, e.g. 'HeLa'. This should reference a term in a controlled vocabulary of cell types. The authors of this publication, one per property value. Defines the molecular weight of the molecule, in daltons. The chemical formula of the small molecule. Note: chemical formula can also be stored in the STRUCTURE property (in CML). In case of disagreement between the value of this property and that in the CML file, the CML value takes precedence. The preferred full name for this entity. For biochemical reactions, this property refers to the standard transformed Gibbs energy change for a reaction written in terms of biochemical reactants (sums of species), delta-G'^o. delta-G'^o = -RT lnK' and delta-G'^o = delta-H'^o - T delta-S'^o delta-G'^o has units of kJ/mol. Like K', it is a function of temperature (T), ionic strength (I), pH, and pMg (pMg = -log₁₀[Mg²⁺]). Therefore, these quantities must be specified, and values for DELTA-G for biochemical reactions are represented as 5-tuples of the form (delta-G'^o T I pH pMg). (This definition from EcoCyc) This property specifies which format is used to define chemical structure data. CML SMILES InChI The name of the external database to which this xref refers. R-L NOT-SPONTANEOUS L-R Specifies whether a conversion occurs spontaneously (i.e. uncatalyzed, under biological conditions) left-to-right, right-to-left, or not at all. If the spontaneity is not known, the SPONTANEOUS property should be left empty. An abbreviated name for this entity, preferably a name that is short enough to be used in a visualization application to label a graphical element that represents this entity. If no short name is available, an xref may be used for this purpose by the visualization application. The integer listed gives the position. The first base or amino acid is position 1. In combination with the numeric value, the property 'POSITION-STATUS' allows to express fuzzy positions, e.g. 'less than 4'. Describes the availability of this data (e.g. a copyright statement). This property holds a string of data defining chemical structure or other information, in either the CML or SMILES format, as specified in property Structure-Format. If, for example, the CML format is used, then the value of this property is a string containing the XML encoding of the CML data. One or more synonyms for the name of this entity. This should include the values of the NAME and SHORT-NAME property so that it is easy to find all known names in one place. Polymer sequence in uppercase letters. For DNA, usually A,C,G,T letters representing the nucleosides of adenine, cytosine, guanine and thymine, respectively; for RNA, usually A, C, U, G; for protein, usually the letters corresponding to the 20 letter IUPAC amino acid code. Temperature in Celsius For biochemical reactions, this property refers to the standard transformed entropy change for a reaction written in terms of biochemical reactants (sums of species), delta-S'^o. delta-G'^o = delta-H'^o - T delta-S'^o (This definition from EcoCyc) The source in which the reference was published, such as: a book title, or a journal title and volume and pages. For biochemical reactions, this property refers to the standard transformed enthalpy change for a reaction written in terms of biochemical reactants (sums of species), delta-H'^o. delta-G'^o = delta-H'^o - T delta-S'^o Units: kJ/mole (This definition from EcoCyc) Comment on the data in the container class. This property should be used instead of the OWL documentation elements (rdfs:comment) for instances because information in COMMENT is data to be exchanged, whereas the rdfs:comment field is used for metadata about the structure of the BioPAX ontology. The version of the external database in which this xref was last known to be valid. Resources may have recommendations for referencing dataset versions. For instance, the Gene Ontology recommends listing the date the GO terms were downloaded. A measure of acidity and alkalinity of a solution that is a number on a scale on which a value of 7 represents neutrality and lower numbers indicate increasing acidity and higher numbers increasing alkalinity and on which each unit of change represents a tenfold change in acidity or alkalinity and that is the negative logarithm of the effective hydrogen-ion concentration or hydrogen-ion activity in gram equivalents per liter of the solution. (Definition from Merriam-Webster Dictionary) A measure of the concentration of magnesium (Mg) in solution. (pMg = -log₁₀[Mg²⁺]) The URL at which the publication can be found, if it is available through the Web. The value of the confidence measure. The external controlled vocabulary term. The title of the publication. This property names the type of relationship between the BioPAX object linked from, and the external object linked to, such as 'gene of this protein', or 'protein with similar sequence'. The confidence status of the sequence position. This could be: EQUAL: The SEQUENCE-POSITION is known to be at the SEQUENCE-POSITION. GREATER-THAN: The site is greater than the SEQUENCE-POSITION. LESS-THAN: The site is less than the SEQUENCE-POSITION. GREATER-THAN LESS-THAN EQUAL The primary identifier in the external database of the object to which this xref refers. The version number of the identifier (ID). E.g. The RefSeq accession number NM_005228.3 should be split into NM_005228 as the ID and 3 as the ID-VERSION. The unique number assigned to a reaction by the Enzyme Commission of the International Union of Biochemistry and Molecular Biology. Note that not all biochemical reactions currently have EC numbers assigned to them. The year in which this publication was published. REVERSIBLE PHYSIOL-RIGHT-TO-LEFT IRREVERSIBLE-LEFT-TO-RIGHT IRREVERSIBLE-RIGHT-TO-LEFT PHYSIOL-LEFT-TO-RIGHT Specifies the reaction direction of the interaction catalyzed by this instance of the catalysis class. Possible values of this slot are: REVERSIBLE: Interaction occurs in both directions in physiological settings. PHYSIOL-LEFT-TO-RIGHT PHYSIOL-RIGHT-TO-LEFT The interaction occurs in the specified direction in physiological settings, because of several possible factors including the energetics of the reaction, local concentrations of reactants and products, and the regulation of the enzyme or its expression. IRREVERSIBLE-LEFT-TO-RIGHT IRREVERSIBLE-RIGHT-TO-LEFT For all practical purposes, the interactions occurs only in the specified direction in physiological settings, because of chemical properties of the reaction. (This definition from EcoCyc) The ionic strength is defined as half of the total sum of the concentration (ci) of every ionic species (i) in the solution times the square of its charge (zi). For example, the ionic strength of a 0.1 M solution of CaCl2 is 0.5 x (0.1 x 22 + 0.2 x 12) = 0.3 M (Definition from http://www.lsbu.ac.uk/biology/enztech/ph.html) ACTIVATION INHIBITION-COMPETITIVE INHIBITION-UNCOMPETITIVE ACTIVATION-ALLOSTERIC ACTIVATION-NONALLOSTERIC INHIBITION-OTHER INHIBITION-NONCOMPETITIVE INHIBITION-IRREVERSIBLE INHIBITION-ALLOSTERIC INHIBITION Defines the nature of the control relationship between the CONTROLLER and the CONTROLLED entities. The following terms are possible values: ACTIVATION: General activation. Compounds that activate the specified enzyme activity by an unknown mechanism. The mechanism is defined as unknown, because either the mechanism has yet to be elucidated in the experimental literature, or the paper(s) curated thus far do not define the mechanism, and a full literature search has yet to be performed. The following term can not be used in the catalysis class: INHIBITION: General inhibition. Compounds that inhibit the specified enzyme activity by an unknown mechanism. The mechanism is defined as unknown, because either the mechanism has yet to be elucidated in the experimental literature, or the paper(s) curated thus far do not define the mechanism, and a full literature search has yet to be performed. The following terms can only be used in the modulation class (these definitions from EcoCyc): INHIBITION-ALLOSTERIC Allosteric inhibitors decrease the specified enzyme activity by binding reversibly to the enzyme and inducing a conformational change that decreases the affinity of the enzyme to its substrates without affecting its VMAX. Allosteric inhibitors can be competitive or noncompetitive inhibitors, therefore, those inhibition categories can be used in conjunction with this category. INHIBITION-COMPETITIVE Competitive inhibitors are compounds that competitively inhibit the specified enzyme activity by binding reversibly to the enzyme and preventing the substrate from binding. Binding of the inhibitor and substrate are mutually exclusive because it is assumed that the inhibitor and substrate can both bind only to the free enzyme. A competitive inhibitor can either bind to the active site of the enzyme, directly excluding the substrate from binding there, or it can bind to another site on the enzyme, altering the conformation of the enzyme such that the substrate can not bind to the active site. INHIBITION-IRREVERSIBLE Irreversible inhibitors are compounds that irreversibly inhibit the specified enzyme activity by binding to the enzyme and dissociating so slowly that it is considered irreversible. For example, alkylating agents, such as iodoacetamide, irreversibly inhibit the catalytic activity of some enzymes by modifying cysteine side chains. INHIBITION-NONCOMPETITIVE Noncompetitive inhibitors are compounds that noncompetitively inhibit the specified enzyme by binding reversibly to both the free enzyme and to the enzyme-substrate complex. The inhibitor and substrate may be bound to the enzyme simultaneously and do not exclude each other. However, only the enzyme-substrate complex (not the enzyme-substrate-inhibitor complex) is catalytically active. INHIBITION-OTHER Compounds that inhibit the specified enzyme activity by a mechanism that has been characterized, but that cannot be clearly classified as irreversible, competitive, noncompetitive, uncompetitive, or allosteric. INHIBITION-UNCOMPETITIVE Uncompetitive inhibitors are compounds that uncompetitively inhibit the specified enzyme activity by binding reversibly to the enzyme-substrate complex but not to the enzyme alone. ACTIVATION-NONALLOSTERIC Nonallosteric activators increase the specified enzyme activity by means other than allosteric. ACTIVATION-ALLOSTERIC Allosteric activators increase the specified enzyme activity by binding reversibly to the enzyme and inducing a conformational change that increases the affinity of the enzyme to its substrates without affecting its VMAX. Each value of this property represents the stoichiometric coefficient for one of the physical entities in an interaction or complex. For a given interaction, the stoichiometry should always be used where possible instead of representing the number of participants with separate instances of each participant. If there are three ATP molecules, one ATP molecule should be represented as a participant and the stoichiometry should be set to 3. The apparent equilibrium constant K'. Concentrations in the equilibrium constant equation refer to the total concentrations of all forms of particular biochemical reactants. For example, in the equilibrium constant equation for the biochemical reaction in which ATP is hydrolyzed to ADP and inorganic phosphate: K' = [ADP][P_i]/[ATP], The concentration of ATP refers to the total concentration of all of the following species: [ATP] = [ATP^4-] + [HATP^3-] + [H₂ATP^2-] + [MgATP^2-] + [MgHATP^-] + [Mg₂ATP]. The apparent equilibrium constant is formally dimensionless, and can be kept so by inclusion of as many of the terms (1 mol/dm³) in the numerator or denominator as necessary. It is a function of temperature (T), ionic strength (I), pH, and pMg (pMg = -log₁₀[Mg²⁺]). (Definition from EcoCyc)