Terms in the MACiE Dictionary

Acceptor

This is the chemical species which accepts something (electrons or another chemical moiety) during the course of a reaction. This is a top level definition, and as such will not be seen in isolation.

Acidic Bimolecular Nucleophilic Substitution

This is a bimolecular nucleophilic substitution, in which the leaving group is protonated prior to the substitution event. The primed group, e.g. a hydroxide group, would otherwise be a poor leaving group. Thus, by protonation, it is made into a much better leaving group. The rate determining step of the reaction involves the collision of two species. In the figure below, the actual substitution is shown enclosed in the blue box.

Acidic Intramolecular Nucleophilic Substitution

This is a intramolecular nucleophilic substitution, in which the leaving group is protonated prior to the substitution event. The primed group, e.g. a hydroxide group, would otherwise be a poor leaving group. Thus, by protonation, it is made into a much better leaving group. The rate determining step of the reaction involves a single species and proceeds via a cyclic transition state.

Activator

A chemical species whose function is to increase the reactivity of another species. Either through an increase, or decrease, the pKa of another species which may be water, another residue, cofactor or substrate, thus activating it for the reaction to occur. It also includes amino acids which effect the electronics of other species.

Addition Reaction

A chemical reaction of two or more reacting molecular entities, resulting in a single reaction product containing all atoms of all components, with formation of at least one chemical bond and a net reduction in bond multiplicity in at least one of the reactants. The following addition reactions are defined in the MACiE dictionary:

	Nucleophilic	Electrophilic	Homolytic
Bimolecular
Aromatic Bimolecular			X
Intramolecular

When the term addition is used in its own, it refers to an addition reaction not covered by the above Ingold reaction mechanisms.

Aldol Addition

A special case of nucleophilic addition. It is the reaction when the enolate of an aldehyde or a ketone reacts at the α-carbon with the carbonyl of another molecule under basic or acidic conditions to obtain a β-hydroxy aldehyde or ketone. It may be either intramolecular or bimolecular. The figure below shows an example of a bimolecular aldol addition.

Amadori Rearrangement

Acid or base catalysed rearrangement of N-glycosides of aldoses to N-glycosides of the corresponding ketoses. An example of this is shown in the figure below.

Amino Acid Residue

In general, amino acid residues in enzymes can be grouped into three broad categories: catalytic, binding (those residues which bind species involved in the reaction) and structural (those not explicitly involved in binding or catalysis). MACiE centres in catalytic residues. All catalytic residues are described as either reactant or spectator, annotated with one or more catalytic functions and the portion of the residue which is catalytic.

Amino Acid Reactant

An amino acid that undergoes a change in either electronic state or covalent bonding in any step of the reaction sequence in which participates. The following functions can be described as reactant only functions:

• functions associated with covalent catalysis: nucleophile, nucleofuge, electrophile, electrofuge, radical combinant and leaving group.
• functions associated with species realy: single electron acceptor, single electron donor, electron pair acceptor, electron pair donor, electron relay, proton acceptor, proton donor, proton relay, hydrogen acceptor, hydrogen donor, hydrogen realy, hydride acceptor, hydride donor and hydride relay.

Reactant residues may also perform any of the spectator functions. Furthermore, in the steps where the reactant residue is not acting, it is considered a spectator residue.

Amino Acid Spectator

An amino acid that exerts an electrostatic or steric effect upon another chemical species which is important for the reaction to occur. This species may be another residue, water molecule, metal ion, substrate, transition state, intermediate or cofactor. There are broadly two types of spectator function annotated in MACiE:

• Interaction types: covalently attached, metal ligand, polar interaction, H-bond acceptor, H-bond donor, attractive charge-charge interaction, repulsive charge-charge interaction, polar/non-polar interaction and van der Waals interaction.
• "True" spectator functions: activtion roles, which include the parent activator role, as well as increase acidity, increase basicity, increase electrophilicity, increase nucleophilicity, promotes heterolytic reactions, promotes homolytic reactions. Other spectator roles include: electrostatic stabiliser, electrostatic destabiliser, radical stabiliser and steric role.

Aromatic Bimolecular Electrophilic Addition (Ad_E2Ar)

A bimolecular electrophilic addition to an aromatic species. This may also be viewed as the first step of an electrophilic aromatic substitution.

Aromatic Bimolecular Elimination (E2Ar)

A bimolecular elimination from an aromatic species.

Aromatic Bimolecular Nucleophilic Addition (Ad_N2Ar)

A bimolecular nucleophilic addition to an aromatic species. This may also be viewed as the first step of a nucleophilic aromatic substitution.

Aromatic Bimolecular Nucleophilic Substitution (S_N2Ar)

A bimolecular nucleophilic substitution upon an aromatic system. It can occur as a two step process: addition of a nucleophilic reagent upon the aromatic ring to form a carbanion, followed by elimination of a nucleofuge, or viceversa, or can occur as a one step process with nucleophilic attack and nucleofuge elimination happening simultaneously.

Aromatic Intramolecular Elimination (EiAr)

An intramolecular elimination reaction from an aromatic species.

Aromatic Unimolecular Elimination by the Conjugate Base (E1cbAr)

An unimolecular elimination by the conjugate base from an aromatic species.

Assisted Keto-Enol Tautomerisation

Keto-enol tautomerisation assisted by proton transfers. The two figures below show the two types of assisted keto-enol tautomerisation in MACiE.

Fully assisted keto-enol tautomerisation	Partially assisted keto-enol tautomerisation

Assisted Other Tautomerisation

Tautomerisation other than keto-enol which is assisted by proton transfers.

Atom Set Involved

Those atoms at which a reaction occurs, such that a bond is either formed, cleaved or altered in order or those atoms at which the electron count changes. This is synomynous with reactive centre.

Attractive Charge-Charge Interaction

Any charged residue that is involved in an attractive charge-charge interaction with another charged species.

Bimolecular Electrophilic Addition (Ad_E2)

An addition of an electrophilic species over a π-bond of another species. The reaction involves the collision of two species in its rate determining step, in the example shown below, the Ad_E2 reactions is shown enclosed in the blue box.

Bimolecular Electrophilic Substitution (S_E2)

An electrophilic substitution which proceeds with second order kinetics i.e. the rate determining step of the reaction involves the collision of two chemical species.

Bimolecular Elimination (E2)

A nucleophilic elimination reaction which proceeds via second order kinetics. The rate determining step involves two chemical species undergoing covalency changes.

Bimolecular Homolytic Addition (Ad_H2)

An addition of a radical species over a π-bond of another species. The reaction involves the collision of two species in its rate determining step.

Bimolecular Homolytic Elimination (E_H2)

A homolytic elimination reaction which proceeds via second order kinetics and involves free radical chemistry. The rate determining step involves two chemical species undergoing covalency changes.

Bimolecular Homolytic Substitution (S_H2)

A homolytic substitution which proceeds with second order kinetics i.e. the rate determining step of the reaction involves the collision of two chemical species.

Bimolecular Nucleophilic Addition (Ad_N2)

An addition of a nucleophilic species over a π-bond of another species. The reaction involves the collision of two species in its rate determining step.

Bimolecular Nucleophilic Substitution (S_N2)

A nucleophilic substitution which proceeds with second order kintetics, i.e. the rate determining step of the reaction involves the collision of two chemical species.

Bimolecular Nucleophilic Substitution with Allylic Rearrangement (S_N2')

This is an S_N2 reaction with concurrent allylic rearrangement of the double bonds in a conjugated system.

Bimolecular Reaction

A chemical reaction involving two molecules.

Bond Cleavage

A mechanism component which states that during the course of the associated reaction one or more covalent bonds are cleaved, either heterolytically or homolytically.

Bond Cleaved

The identity of the bond cleaved during the course of a reaction.

Bond Formation

A mechanism component which states that during the course of the associated reaction, one or more covalent bonds are formed, either heterolytically or homolytically.

Bond Formed

The identity of the bond formed during the course of a reaction.

Bond Involved

The identity of the bond that changes stereochemistry during the course of an overall reaction.

Bond Order Change

A mechanism component which states that during the course of the associated reaction one or more bonds undergo a change of order.

Bond Order Changed

The identity of the bond which is altered during a bond order change. This bond is always found in conjunction with its starting bond order and final bond order.

Bond Polarisation

A mechanism component which states that during the course of the associated reaction a charge is formed over a bond, or set of atoms which may involve more than one bond.

Bond Polarised

The identity of the bond which is polarised during the course of a reaction.

Bond Set Involved

Those bonds that are involved in the reaction, i.e. those bonds which undergo some change. This is synomynous with reactive centre.

Brønsted Acids and Bases

A Brønsted acid, represented by the "A" in the figure below, is a chemical species which is capable of donating a proton.

A Brønsted base, represented by the "B" in the figure above, is a chemical species which has an available pair of electrons capable of forming a covalent bond with a proton.

Catalytic CATH Code

The CATH code(s) associated with the catalytic domain(s) in the protein.

CATH is a hierarchical classification of protein domain structures, which clusters proteins at four major levels, Class(C), Architecture(A), Topology(T) and Homologous superfamily (H). More information on CATH can be found at http://www.cathdb.info/latest/index.html.

Catalytic Residue List

List of catalytic residues in the overall annotation of the MACiE entries.

Catalytic UniProt Code

The UniProt code(s) associated with the catalytic chain(s) of the protein.

UniProt (Universal Protein Resource) is the world's most comprehensive catalog of information on proteins. It is a central repository of protein sequence and function created by joining the information contained in Swiss-Prot, TrEMBL, and PIR. More information on UniProt can be found at http://www.ebi.uniprot.org/index.shtml.

CATH Code

The CATH code(s) associated with the domain(s) not listed as catalytic.

CATH is a hierarchical classification of protein domain structures, which clusters proteins at four major levels, Class(C), Architecture(A), Topology(T) and Homologous superfamily (H). More information on CATH can be found at http://www.cathdb.info/latest/index.html.

Charge Delocalisation

A mechanism component which states that during the course of the associated reaction a charge spreads out over a number of bonds in a chemical species.

Charge Delocalised Over

The identity of the atoms over which charge is delocalised during the course of a reaction.

Charge Destabiliser

A chemical species whose function is to destabilise positive or negative charge that has built during the course of a reaction step.

Charge Stabiliser

A chemical species whose function is to stabilise positive or negative charge that has built during the course of a reaction step.

ChEBI Identifier

ChEBI identifier for a metabolite or other chemical compound structure.

Chemical Entities of Biological Interest (ChEBI) is a freely available dictionary of molecular entities focused on 'small' chemical compounds. The term 'molecular entity' refers to any constitutionally or isotopically distinct atom, molecule, ion, ion pair, radical, radical ion, complex, conformer, etc., identifiable as a separately distinguishable entity. The molecular entities in question are either products of nature or synthetic products used to intervene in the processes of living organisms. ChEBI can be found at: http://www.ebi.ac.uk/chebi/. Wherever possible in MACiE, molecules are given a ChEBI identifier.

Claisen Rearrangement

Highly stereoselective thermally allowed [3,3]-sigmatropic rearrangement of allyl vinyl or allyl aryl ethers. Usually intramolecular, the mechanism is somewhat similar to that of the Diels-Alder.

Co-factor

A chemical species which is required in order for the enzyme to be active. Some cofactors undergo change in either electronic state or covalent bonding, but they are regenerated during the course of the reaction. This differs from coenzymes which are used by the enzymes and regenerated elsewhere. The latter are listed as substrates/products of the reaction rather than cofactors.

Cofactor Regenerated

A mechanism component which states that during the course of the associated reaction a molecule listed as a cofactor (in the overall reaction) is returned to a state in which it is able to undergo another round of catalysis.

Cofactor Used

A mechanism component which states that during the course of the associated reaction a molecule listed as a cofactor (in the overall reaction) is initially used.

Colligation

This is the formation of a bond such that each of the molecular fragments between which the bond is formed donate one of the bonding electrons. This is the reverse of a homolysis reaction.

Coordination

A reaction in which a single bond is formed by the reaction of two oppositely charged ions. This is the reverse of a heterolysis reaction.

Covalently Attached

The chemical species is covalently attached to a substrate or intermediate of the reaction, forming an enzyme-substrate covalent bond.

Cyclisation

The formation of a ring compound from a chain by the formation of a new bond.

Deamination

A mechanism component which states that in the associated reaction ammonia is one of the products.

Decarboxylation

A mechanism component which states that in the associated reaction carbon dioxide is one of the products.

Decyclisation

The formation of a chain compound from a ring by the cleavage of an existing bond.

Dehydration

A mechanism component which states that in the associated reaction water is one of the products.

Dephosphorylation

A mechanism component which states that in the associated reaction phosphate, pyrophosphate or triphosphate is one of the products.

Donor

A chemical species which donates something (electrons or some other chemical moiety) to a reaction during the course of the reaction. This is a top level definition, and as such is not seen in isolation.

EC Number

The Enzyme Commission (EC) classification number associated with the overall reaction catalysed by an enzyme.

The EC classification number was developed by the EC in 1961. It relies upon the overall reaction, substrates and products, as well as the reaction direction to classify the enzyme in a four level system. The top level is called the class, the second level the sub-class, the third level the sub-subclass and the final level is called the serial number. Taken together, class, sub-class, and sub-subclass define the chemistry catalysed by an enzyme. Conversely, the serial number often denotes substrate specificity. More information can be found at http://www.chem.qmul.ac.uk/iubmb/enzyme/.

Electrofuge

An electrofuge is a leaving group which does not carry away the bonding electrons.

Electron Acceptor

This is the chemical species which accepts electrons during the course of a reaction. This is a top level definition, and as such not seen in isolation, the more specific terms associated with this are single electron acceptor and electron pair acceptor.

Electron Donor

This is the chemical species which donates electrons during the course of a reaction. This is a top level definition, and as such not seen in isolation, the more specific terms associated with this are single electron donor and electron pair donor.

Electron Pair Acceptor

This is the chemical species which accepts two electrons during the course of a reaction.

Electron Pair Donor

This is the chemical species which donates two electrons during the course of a reaction.

Electron Relay

A mechanism component which states that the associated reaction contains an electron relay, i.e. a chemical species that both accepts and donates electrons during the course of the reaction. This term also applies to the residue that performs this role and is synonymous with the Catalytic Site Atlas term electron tunnelling medium.

Electron Transfer

A reaction in which an electron is transferred from one reacting species to another.

Electrophile

An electrophile is a chemical species that forms a bond to its reaction partner (the nucleophile) by accepting both bonding electrons from that reaction partner. This is synonymous to Lewis acid.

Electrophilic Reaction

A reaction in which the reagent acts as an electrophile.

Electrostatic Destabiliser

A chemical species whose function is to exert a repulsive electrostatic interaction upon charges developing during the course of a reaction step.

Electrostatic Stabiliser

A chemical species whose function is to exert an attractive electrostatic interaction upon charges developing during the course of a reaction step.

Elimination Reaction

In an elimination, one or more groups are lost, most often from two different centres with concomitant formation of an unsaturation in the molecule (double bond, triple bond) or the formation of a new ring. The following elimination reactions are defined in the MACiE dictionary:

	Nucleophilic	Homolytic
Bimolecular
Aromatic Bimolecular		X
Intramolecular
Aromatic Intramolecular		X
Unimolecular
Aromatic Unimolecular		X

When the term elimination is used in its own, it refers to an elimination reaction not covered by the above Ingold reaction mechanisms.

Enzyme Name

Name of the enzyme. In MACiE this is always the Common name as recommended by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology. For more information on naming enzymes see the http://www.chem.qmul.ac.uk/iubmb/enzyme/.

Enzyme Not Regenerated

The enzyme is not returned to its ground state, or a state in which it is ready to perform another catalytic cycle, by the end of this reaction. This term is found both in the overall reaction annotation, and step annotation. When it is found in the step annotation, it is applied to the final step in which a change occurs in the enzyme.

Enzyme Regenerated

The enzyme is returned to its ground state, or a state in which it is ready to perform another catalytic cycle, by the end of this reaction. This term is found both in the overall reaction annotation, and step annotation. When it is found in the step annotation, it is applied to the final step in which a change occurs in the enzyme.

Enzyme-Substrate Bond Cleavage

One or more covalent bonds between the enzyme and substrate are cleaved, either heterolytically or homolytically, during the associated reaction.

Enzyme-Substrate Bond Formation

One or more covalent bonds between the enzyme and substrate are formed, either heterolytically or homolytically, during the associated reaction.

Evidence

Evidence of amino acid function and catalytic mechanisms. It can be be taken from literature references or the crystal structure used.

EzCatDB Identifier

The EzCatDB code associated with the overall reaction catalysed by the enzyme.

The EzCatDB database analyses and classifies the enzyme catalytic mechanisms, based on information from literature, and derived data from entries in the Protein Data Bank (PDB), for more information see http://mbs.cbrc.jp/EzCatDB/.

Final Bond Order

The final order of a bond implicated in a bond formation, bond cleavage or bond order change.

Metal Centre Geometries

Capped Octahedron

This is a molecular geometry with seven coordinate geometry.

Capped Trigonal Prism

This is a molecular geometry with seven coordinate geometry.

Octahedral

This is a molecular geometry with six atoms or groups of atoms or ligands are symmetrically arranged around a central atom, defining the vertices of an octahedron. A perfect octahedron belongs to the point group O_h. The bond angles in a perfect octahedron are 90 degrees.

Pentagonal Bipyramidal

This is a molecular geometry with one atom at the centre with seven ligands at the corners of a pentagonal dipyramid. A perfect pentagonal bipyramid belongs to the molecular point group D_5h. The pentagonal bipyramid is a case where bond angles surrounding an atom are not identical.

Square Planar

This molecular geometry describes molecules that have their atoms positioned at the corners of a square on the same plane about a central atom.

Square Pyramidal

This square based pyramidal geometry describes the shape of certain compounds with the formula ML₅ where L is a ligand.If the ligand atoms were connected, the resulting shape would be that of a pyramid with a square base. The geometry is common for certain main group compounds that have a stereochemically active lone pair.

Tetrahedral

This is a molecular geometry with one atom at the centre and four atoms at the corners of a pyramid, with no extra unshared electron pairs. In an ideal tetrahedral species, the bond angles are 109.5 degrees.

Trigonal Bipyramidal

This is a molecular geometry with one atom at the center and five more atoms at the corners of a triangular dipyramid. This is one of the only cases where bond angles surrounding an atom are not identical, simply because there is no geometrical arrangement which can result in five equally sized bond angles in three dimensions.

Trigonal Planar

This is a molecular geometry with one atom at the centre and three atoms at the corners of a triangle all in one plane. In an ideal trigonal planar species, all three ligands are identical and all bond angles are 120 degrees and belong to the point group D_3h.

Trigonal Pyramidal

This is a molecular geometry with one atom at the apex and three atoms at the corners of a trigonal base.

T-Shaped

This molecular geometry describes a somewhat unusual geometry adopted by compounds where a central atom has three ligands. Ordinarily, three-coordinated compounds minimize the steric repulsion between the ligands by adopting trigonal planar geometry. According to VSEPR theory this geometry results from three ligands and two lone pairs of electrons bonded to the central atom. The three atoms bond at 90 degree angles on one side of the central atom, producing the T shape.

Unknown Geometry

The species has an unknown geometry. This is most likely due to a lack of crystal structures for this species.

Group Transfer Reactions

A reaction in which a chemical moiety is transferred from one reacting species to another. Includes electron transfer, hydride transfer, hydrogen transfer and proton transfer. These reactions are not included in the Ingold nomenclature as they are substitutions at a single entity, and as such, it is considered inappropriate to call them substitutions.

Heterolysis

The cleavage of a covalent bond so that both bonding electrons remain with one of the two fragments between which the bond is broken. This is the reverse of a coordination reaction.

Heterolytic Reaction

A reaction in which the bonds are split unequally, with both bonding electrons ramaining with one of the atoms, also known as ionic reactions. These reactions are further divided into nucleophilic and electrophilic reactions.

Homolysis

The cleavage of a bond so that each of the molecular fragments between which the bond is broken retains one of the bonding electrons. This is the reverse of a colligation reaction.

Homolytic Reaction

A reaction in which the bonds are split equally, with one electron staying on each of the atoms, also known as free radical reactions.

Hydride Acceptor

A chemical species that accepts a hydride during the course of the reaction.

Hydride Donor

A chemical species that donates a hydride during the course of the reaction.

Hydride Relay

The reaction contains a hydride relay, i.e. a chemical species that both accepts and donates a H^- during the course of the reaction. This term also applies to the residue that performs this role.

Hydride Transfer

A reaction in which a hydride is transferred from one reacting species to another.

Hydrogen Acceptor

Chemical species which accepts a hydrogen atom during the course of the reaction.

Hydrogen Bond Acceptor

Chemical species contains a nitrogen, oxygen, sulphur, or halogen atom with at least one available lone pair. This then forms a weak interaction with an entity containing a nitrogen, oxygen or sulphur atom which is covalently bound to at least one hydrogen atom.

Hydrogen Bond Donor

Chemical species contains a nitrogen, oxygen or sulphur atom which is covalently bound to at least one hydrogen atom. This then forms a weak interaction with an entity which contains a nitrogen, oxygen, sulphur or halogen with at least one available lone pair.

Hydrogen Donor

Chemical species which donates a hydrogen atom during the course of the reaction.

Hydrogen Relay

This reaction contains a hydrogen relay, i.e. a chemical species that acts as both hydrogen acceptor and hydrogen donor during the course of the reaction. This term also applies to the residue that performs this role.

Hydrogen Transfer

A reaction in which a hydrogen atom is transferred from one reacting species to another.

Hydrolysis

A reaction during which nucleophilic attack by water leads to the cleavage of one or more bonds in a reactant.

Increase Acidity

The chemical species is decreasing the pK_a of one of the reactive centres by means of electrostatic interactions.

Increase Basicity

The chemical species is increasing the pK_a of one of the reactive centres by means of electrostatic interactions.

Increase Electrophilicity

The chemical species is increasing the electrophilicity of one of the reactive centres by means of electrostatic interactions.

Increase Nucleophilicity

The chemical species is increasing the nucleophilicity of one of the reactive centres by means of electrostatic interactions. This is currently only used for cofactors.

Inferred Step

A reaction step which has been inferred from the literature entries. These steps normally consist only of "obvious" proton transfers and have been added in order to return the enzymes to their resting states (inferred return steps). There are also reactions such as transaldiminations and Schiff base formations which are commonly not cited as a stepwise reaction in the literature references, and we have had to infer their step-by-step mechanisms.

Ingold Mechanisms

A description of mechanisms using three basic descriptors:

1. The structural changes undergone by the reactants
   • Addition
   • Elimination
   • Substitution
2. The type of reaction according to the class to which the reagent belongs
   • Homolytic
   • Heterolytic
     1. Nucleophilic
     2. Electrophilic
3. Molecularity
   • Unimolecular
   • Bimolecular
   • Intramolecular

Intermediate

Chemical species with a lifetime appreciably longer than a molecular vibration that is formed from the reactants and reacts further to give the products of a chemical reaction, or another intermediate.

Intermediate Collapse

A reaction in which an intermediate collapses to form two or more species, which may be a product or another intermediate.

Intermediate Collapsed

The identity of those intermediates collapsed during the course of a reaction.

Intermediate Formation

A reaction in which an intermediate is formed.

Intermediate Formed

The identity of those intermediates formed during the course of a reaction.

Intermediate Terminated

A reaction in which an intermediate only forms a product of the overall reaction.

Intramolecular Electrophilic Addition (Ad_Ei)

An addition of an electrophilic moiety of a species over a π-bond of the same species. The reaction proceeds via a cyclic transition state.

Intramolecular Electrophilic Substitution (S_Ei)

An electrophilic moiety in a species substitutes another electrophilic moiety from the same species. The reaction proceeds via a cyclic transition state.

Intramolecular Elimination (Ei)

A nucleophilic elimination reaction in which all the components are in the same chemical species. The reaction proceeds via a cyclic transition state.

Intramolecular Homolytic Addition (Ad_Hi)

An addition of a radical moiety of a species over a π-bond of the same species. The reaction proceeds via a cyclic transition state.

Intramolecular Homolytic Elimination (E_Hi)

A homolytic elimination reaction in which all the components are in the same chemical species. The reaction proceeds via a cyclic transition state.

Intramolecular Homolytic Substitution (S_Hi)

A radical moiety in a species substitutes another radical moiety from the same species. The reaction proceeds via a cyclic transition state.

Intramolecular Nucleophilic Addition (Ad_Ni)

An addition of a nucleophilic moiety of a species over a π-bond of the same species. The reaction proceeds via a cyclic transition state.

Intramolecular Nucleophilic Substitution (S_Ni)

A nucleophilic moiety in a species substitutes another nucleophilic moiety from the same species. The reaction proceeds via a cyclic transition state.

Intramolecular Nucleophilic Substitution with Allylic Rearrangement (S_Ni')

This is an S_Ni reaction with concurrent allylic rearrangement of the double bonds in a conjugated system.

Intramolecular Reaction

A chemical reaction involving a single molecule reacting with itself.

Intramolecular Rearrangement

The term is traditionally applied to any reaction that involves a change of connectivity (sometimes including hydrogen), and violates the so-called principle of minimum structural change.

Isomerisation

A reaction in which the principal product is isomeric with the principal reactant.

KEGG Number

This is the C (or compound) number assigned to a chemical species in the KEGG (Kyoto Encyclopedia of Genes and Genomes) Ligand databases. More information about KEGG can be found at http://www.genome.jp/kegg/.

Keto-Enol Tautomerisation

Tautomerisation of the form: H-C-C=O <=> C=C-O-H

Leaving Group

An atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate. This term is used for leaving groups which carry away only one of the bonding electrons.

Lewis Acids and Bases

A Lewis acid, represented by AlCl₃ in the diagram below, is a chemical species which is short of an octect of electrons by one or more electron pairs, and so can accept a pair of electrons by forming a covalent bond. This is synonymous to electrophile.

A Lewis base, represented by Cl^- in the diagram above, is a chemical species which has an available pair of electrons and so can donate it to form a covalent bond with the vacant orbital of a Lewis acid. This is synonymous to nucleophile.

Literature Reference

A reference from the literature which has been used to annotate a MACiE entry. Wherever possible literature references are associated to their PubMed identifiers.

Location of Residue Function

The portion of the catalytic residue that is involved in catalysis. In MACiE we define the following catalytic portions:

• Side chain or R group
• Main chain amide
• Main chain carbonyl
• Main chain C_α
• Main chain C-terminus
• Main chain N-terminus
• Post-translatinally modified

MACiE Identifiers

Identifiers used within MACiE. These include the Unique MACiE ID, EC number, PDB code, enzyme name, species common name, species scientific name, EzCatDB identifier, SFLD identifier, catalytic UniProt code(s), non-catalytic UniProt code(s), catalytic CATH code(s) and non-catalytic CATH code(s).

Main Chain

An amino acid residue performing a catalytic function via either its main chain amide, main chain carbonyl, Cα moiety, or even the C-terminus or N-terminus portion of the terminal residue.

Main Chain Amide

The NH group on the polypeptide backbone.

Main Chain Cα

The C_α atom on the polypeptide backbone.

Main Chain C Terminus

The carboxylate group at the C-terminus of the polypeptide backbone.

Main Chain Carbonyl

The C=O group on the polypeptide backbone.

Main Chain N Terminus

The amine group at the N-terminus of the polypeptide backbone.

Main Class of E.C. Classification

Main class of the enzyme in the E.C. classification system. This can be any number between one and six and represents the top level classification of the enzyme according to the EC:

1. Oxidoreductases
2. Transferases
3. Hydrolases
4. Lyases
5. Isomerases
6. Ligases

Mechanism

A textual description of the "curly arrow" notation used in organic chemistry. In MACiE, these are described, wherever possible, in terms of the classic Ingold mechanisms of organic chemistry. However, we also make provision for group transfer reactions, named organic reactions and other reactions to describe some of the mechanisms.

Mechanism Components

A diverse set of descriptors that capture all the non-mechanistic attributes of the chemical reaction happening in a step. The mechanism components found in MACiE can be divided into six groups:

• Bonds - bond cleavage, bond formation, bond order change, bond polarisation, enzyme-substrate bond cleavage, enzyme-substrate bond formation, metal coordination, and metal decoordination.
• Relays - electron relay, hydride relay, hydrogen relay, and proton relay.
• Regeneration of the catalytic species involved in the reaction - cofactor regenerated, cofactor used, enzyme not regenerated, and enzyme regenerated.
• Substrates, intermediates, products - intermediate collapse, intermediate formation, intermediate terminated, overall product formed, and overall reactant used.
• General consequences - charge delocalisation, cyclisation, deamination, decarboxylation, decyclisation, dehydration, dephosphorylation, and hydrolysis.
• Other descriptions - inferred step, reaction occurs outside, and Schiff base formed.

Metal Coordination

A species coordinatesto a metal ion during the course of this reaction.

Metal De-coordination

A species de-coordinates from a metal ion during the course of this reaction.

Metal Ligand

The residue is bound to a metal ion as a ligand of that ion. This function is only assigned when the amino acid is catalytic, i.e. performing a simultaneous function. If a residue is only ligating a metal, it is not included in the annotation.

Michael Addition

1,4-nucleophilic addition. Occurs on addition of a "soft" nucleophile to an alpha-beta unsaturated carbonyl compound.

Molecularity

The number of reactant species involved.

Named Organic Reaction

Reactions, most often consisting of a number of succesive steps, which are given particular names. In MACiE there are three named organic reactions: aldol addition, Amadori rearrangement and Claisen rearrangement.

Nucleofuge

A nucleofuge is a leaving group which does carry away the bonding electrons.

Nucleophile

A nucleophile is a chemical species that forms a bond to its reaction partner (the electrophile) by donating both bonding electrons. This is synonymous to Lewis Base.

Nucleophilic Reaction

A reaction in which the reagent acts as a nucleophile.

Other Reactions

These reactions do not fall into Ingold mechanisms, group transfer reactions or named organic reactions. These include: assisted keto-enol tautomerisation, assisted other tautomerisation, colligation, coordination, heterolysis, homolysis, isomerisation, keto-enol tautomerisation, other tautomerisation, pericyclic reaction, photochemical activation, radical formation, radical propagation, radical termination, redox, and sigmatropic rearrangement.

Other Tautomerisation

Tautomerisations not of the form: H-C-C=O <=> C=C-O-H

Overall Annotation

Annotation relating to the overall reaction.

Overall Annotation Comments

Comments made by the annotators in relation to the overall reaction.

Overall Product

A final product of the overall reaction catalysed by an enzyme as defined by the Enzyme Commission.

Overall Product Formed

An overall product of the enzyme reaction is produced in this step. The step may be producing either the overall product itself, or the result of the enzymatic reaction, which then undergoes some spontaneous change, not necessarily occurring within the enzyme, to form one of the overall products.

Overall Reactant

An initial reactant of the overall reaction catalysed by an enzyme as defined by the Enzyme Commission.

Overall Reactant Used

An overall reactant of the enzyme is consumed in this step. The step may be using either the overall reactant itself or the result of some spontaneous change on one of the overall reactants which occurs just prior to the enzymatic reaction.

Overall Reaction

This is a reduced view of the complete transformation occuring in a MACiE entry, equivalent to the reaction description of the Enzyme Commission. In MACiE, this is described by a sequence of stepwise reactions making up the reaction sequence.

Pericyclic Reaction

Chemical reaction in which concerted reorganization of bonding takes place throughout a cyclic array of continuously bonded atoms. An example of a pericyclic reaction is the Claisen rearrangement, shown below.

Photochemical Activation

The activation of a chemical species by light.

Polar Interaction

Any polar residue which is involved in a polar-polar interaction with another polar species, including both attractive and repulsive forces. Interactions through hydrogen bonds are special cases of polar interactions.

Polar/Non-Polar Interaction

Any polar or non-polar residue which is involved in a non-covalent interaction with another non-polar or polar chemical species, respectively.

Post-Translatinally Modified

An amino acid residue performing its catalytic function via a chemical moiety that has been added to it after translation of the protein.

Previous EC Number

Previous Enzyme Commission classification number. The Enzyme Commission regularly updates its lists of EC numbers, and therefore the numbers originally assigned to an enzyme may change. This represents a way of tracking previous EC numbers in MACiE, which are sometimes more appropriate for tracking PDB entries.

Primary PDB Code

PDB code which relates directly to the MACiE entry. There is only one PDB code assigned per enzyme, unless different domains of one enzyme span more than one pdb code. In that case there will be two primary PDB codes cited.

Product

A chemical species which is formed during the course of the observed reaction.

Protein Sequence from PDB

Single letter amino acid code of protein sequence taken from PDB file.

Promotes Heterolytic Reactions

Chemical species which promotes the heterolytic cleavage of a bond in the reaction.

Promotes Homolytic Reactions

Chemical species which promotes the homolytic cleavage of a bond in the reaction.

Proton Acceptor

Chemical species which accepts a proton from another chemical species involved in a reaction step. This term is synonymous with general base and Brønsted base.

Proton Donor

Chemical species which donates a proton to another residue, substrate, cofactor or other moiety involved in a reaction step. This term is synonymous with general acid and Brønsted acid.

Proton Relay

The reaction contains a proton relay, i.e. a chemical species that acts as both Brønsted base and Brønsted acid during the course of the reaction. This term also applies to the residue that performs this role.

Proton Transfer

A reaction in which a proton is transferred from one reacting species to another.

PubMed Identifier

The identifier given in PubMed to the literature references used for a MACiE entry.

To find out more about PubMed visit the PubMed website.

Radical Combinant

This is the chemical species which combines with another species in a radical reaction to form a covalent bonded species. This is typically used as cofactor annotation for flavins reacting with molecular oxygen to generate 4a-hydroperoxy species. This is also used as the function of residues in AdH2 reactions.

Radical Formation

A reaction in which the initial generation of free radicals occurs.

Radical Propagation

A reaction in which the free radical causes some chemical change, but it is not lost.

Radical Stabiliser

Chemical species which stabilises a free radical carrying species during the course of the reaction.

Radical Termination

A reaction in which the free radical is lost.

Rate-Determining Step

This is the step in a reaction which has the slowest rate, thus imposing an upper limit on the overall reaction rate. In a MACiE catalytic step RDS can take the value of unknown, yes or no.

Reacting Species

These are the species which are involved in the reaction and undergo a change in either electronic state or covalent bonding.

Reaction

A process that results in the interconversion of chemical species.

Reaction Attribute

A diverse set of descriptors that capture all the non-mechanistic attributes of the chemical reaction happening in a step. This is synonymous to Mechanism Components.

Reaction Occurs Outside the Enzyme

A reaction which occurs outside of the enzyme and that is generally spontaneous. These steps are included in MACiE because they either spontaneously form the enzyme's substrate from the overall reactants of the reaction as defined by EC or form the overall products of the EC reaction from an intermediate generated by the enzyme.

Reaction Mechanism

Detailed chemical description of the whole process involved in converting reactants to products. Made up out of reaction steps, described in terms of mechanisms, mechanism components and the functions performed by all catalytic amino acid residues in each step.

Reaction Scheme

The complete chemical reaction made up of the overall reaction and reaction steps.

Reaction Scheme Metadata

The metadata relating to the overall reaction scheme.

Reaction Sequence

A complete set of reaction steps describing an overall reaction.

Reaction Step Metadata

Metadata associated with an individual reaction step.

Reaction Step

An individual stepwise reaction representing a probable local minimum on the reaction pathway.

Reaction Type

This is synonimous to mechanism.

Reactive Centre

Those atoms at which a reaction occurs, such that a bond is either formed, cleaved or altered in order or those atoms at which the electron count changes.

Redox

A reaction in which a one electron transfer occurs to generate a radical.

Reference List

List of the literature references used.

Repulsive Charge-Charge Interaction

Any charged residue which is involved in a repulsive charge-charge interaction with another charged species.

Residue Function

The function performed by an amino acid residue. These functions depend on whether the residue ia a reactant or spectator.

Reversibility

A reaction which can proceed in the forward direction as readily as in the reverse direction. In a MACiE catalytic step reversibility can take the value of unknown, yes or no.

Schiff Base Formed

A mechanism component which states that during the course of the associated reaction there is a formation of an imine bearing a hydrocarbyl group on the nitrogen atom.

Serial Number of E.C. Classification

The serial number of the enzyme in its sub-subclass. This represents the final level of classification in the E.C. system. When combined with the previous three numbers it gives a unique number to the enzyme classified. The serial number often specifies the substrate specificity of an enzyme, however is semantically meaningless.

Structure Function Linkage Database (SFLD) Identifier

The SFLD code associated with the overall reaction catalysed by the enzyme.

The SFLD database focuses in the catalytic mechanisms of mechanistically diverse enzyme superfamilies. For more information see http://sfld.rbvi.ucsf.edu/.

Side Chain

An amino acid residue performing its catalytic function via its side chain moiety (or R group).

Single Electron Acceptor

This is the chemical species which accepts one electron during the course of a reaction.

Single Electron Donor

This is the chemical species which donates one electron during the course of a reaction.

Sigmatropic Rearrangement

Molecular rearrangement involving both the creation of a new σ-bond between atoms previously not directly linked and the breaking of an existing σ-bond. Often accompanied by a concurrent relocation of π-bonds in the molecule, however the total number of π- and σ- bonds remains the same.

Species Activated

A chemical species whose reactivity is increased during the course of the reaction.

Species Common Name

Common name of the source organism of the enzyme.

Species Oxidised

This is the chemical species which undergoes oxidation (loss of electrons) during the course of a redox reaction.

Species Reduced

This is the chemical species which undergoes reduction (gain of electrons) during the course of a redox reaction.

Species Scientific Name

Scientific name of the source organism of the enzyme.

Spectator

These are the species which are involved in the reaction but do not undergo a change in either electronic state or covalent bonding. These molecules exert an electrostatic or steric effect upon another chemical species which is important for the reaction to occur. This species may be another residue, water molecule, metal ion, substrate, transition state, intermediate or cofactor.

Starting Bond Order

The initial order of a bond implicated in a bond formation, bond cleavage or bond order change.

Step Annotation

Annotation associated with an individual reaction step.

Step Annotation Comments

Comments made by the annotators in relation to an individual reaction step.

Steric Role

The chemical species perturbs the reactive species in a purely steric manner to induce reaction. This can be either purely perturbative, undefined or hindering due to the bulk of the species.

Subclass of EC Classification

The subclass of the enzyme. This represents the second level of the EC classification, the definition of this number depends on the first level of classification. 99 is used when the category of the sub-subclass is unknown.

Substitution Reaction

A reaction, either elementary or stepwise, in which one atom or group in a molecular entity is replaced by another atom or group. The following substitution reactions are defined in the MACiE dictionary:

	Nucleophilic	Electrophilic	Homolytic
Bimolecular
Aromatic Bimolecular		X	X
Intramolecular

In addition to the above types of substitutions, there also exist the acidic S_N2, acidic S_Ni, allylic S_N2 and allylic S_Ni. When the term substitution is used in its own, it refers to a substitution reaction not covered by the above Ingold reaction mechanisms.

Substrate

A chemical species which is consumed during the course of the observed reaction.

Sub-subclass of EC Classification

The sub-subclass of the enzyme. This represents the third level of EC classification, the definition of this number depends on the first two levels of EC classification. 99 is used when the category of the sub-subclass is unknown.

Tautomerisation

Isomerism of the general form GXY=Z <=> X=YZG where the isomers are readily inter-convertible; the atoms connecting the groups X,Y,Z are typically any of C, H, O or S, and G is a group which becomes an electrofuge or nucleofuge during isomerisation. The example below is a keto-enol tautomerisation

Transition State

The state in which an assembly of atoms, when randomly placed there, would have an equal probability of forming the reactants or of forming the products of the elementary reaction. This is not an isolatable state, unlike an intermediate.

TyMeS Code

The classification code developed for MACiE, it represents the Type of the reaction, the Mechanism of the reaction and the Similarity of the reaction to others in the same top two classes.

Unimolecular Elimination by the Conjugate Base (E1cb)

A unimolecular elimination reaction in which a conjugate base species eliminates an atom or group from itself to form a double bond (or cyclic compound). The actual E1cb is shown in the blue box in the image below.

Unimolecular Homolytic Elimination (EH1)

A homolytic unimolecular elimination reaction in which a radical moiety eliminates another radical moiety from the same species by forming a double bond (or cyclic compound). The rate determining step involves a single species.

UniProt Code

The UniProt code(s) associated with the chain(s) of the protein not listed as catalytic

UniProt (Universal Protein Resource) is the world's most comprehensive catalog of information on proteins. It is a central repository of protein sequence and function created by joining the information contained in Swiss-Prot, TrEMBL, and PIR. More information on UniProt can be found at http://www.ebi.uniprot.org/index.shtml.

Unique MACiE Overall ID

Unique MACiE ID for each entry. This takes the form of an "M" followed by four digits, e.g. M0001.

Unique MACiE Step ID

Unique MACiE ID for each step. This takes the form of the Unique MACiE Overall ID plus the string "_stg" followed by two digits, e.g. M0001_stg01.

Unimolecular Reaction

A chemical reaction only involving a single molecule.

Unknown Function

The amino acid's function is not know for this reaction, although it is suspected that it may play an active part.

Van der Waals Interaction

Any non-polar residue which is involved in a non-covalent interaction with another non-polar chemical species. This includes aromatic π-stacking and the stabilisation of non-polar radical species by the excess π-electrons of an aromatic species.

X Number

This is a code associated with a specific chemical species in MACiE which does not have a corresponding KEGG Number. A full list of the X number currently found in MACiE can be found here.