The enzyme commission classification

The best known detailed classification of protein functions is that of the Enzyme Commission (EC) (http://www.chem.qmul.ac.uk/iubmb/enzyme/). The EC classification originated in the action taken by the General Assembly of the International Union of Biochemistry (IUB) and the International Union of Pure and Applied Chemistry (IUPAC), in 1955, to establish an International Commission on Enzymes.

EC numbers (looking suspiciously like IP numbers) contain four fields, corresponding to a four-level hierarchy. For example, EC 1.1.1.1 corresponds to alcohol dehydrogenase, catalysing the general reaction an alcohol + NAD = the corresponding aldehyde or ketone + NADH

Several reactions, involving different alcohols, would share this number; but the same dehydrogenation of one of these alcohols by an enzyme using the alternative cofactor NADP would be assigned EC 1.1.1.2. The Commission has emphasized that 'It is perhaps worth noting, as it has been a matter of long-standing confusion, that enzyme nomenclature is primarily a matter of naming reactions catalysed, not the structures of the proteins that catalyse them'. The EC merges nonhomologous enzymes that catalyse similar reactions.

The first number indicates one of six main divisions:

Class

1.

Oxidoreductases

Class

2.

Transferases

Class

3.

Hydrolases

Class

4.

Lyases

Class

5.

Isomerases

Class

6.

Ligases.

The significance of the second and third numbers depends on the class. The fourth number gives the specific enzymatic activity.

Granting its groundbreaking achievement, there is consensus that the EC classification has many drawbacks that limit its utility for contemporary work.

Specialized classifications are available for some families of enzymes; for instance, the MEROPS database by N.D. Rawlings and A.J. Barrett provides a structure-based classification of peptidases and proteinases (http://www.merops.sanger.ac.uk/).

Given the goal of mapping a functional classification onto sequence and structure classifications, several problems associated with current functional categorizations are generally recognized. Gerlt and Babbitt (2000), who are among the most thoughtful writers on the subject, pointed out that 'no structurally contextual definitions of enzyme function exist'. They propose a general hierarchical classification of function better integrated with sequence and structure. For enzymes they define the following.

• Family: homologous enzymes that catalyse the same reaction (same mechanism same substrate specificity). These can be hard to detect at the sequence level if the sequence similarity becomes very low.

• Superfamily: homologous enzymes catalysing similar reaction with either (a) different specificity or (b) different overall reactions with common mechanistic attribute (partial reaction, transition state, intermediate) that share conserved active-site residues.

• Suprafamilies: different reactions with no common feature. Proteins belonging to the same suprafamily would not be expected to be detectable from sequence information alone.

There is also a 'culture clash': the traditional biochemist's view of function arises from the study of isolated proteins in dilute solutions; to a molecular biologist, an adequate definition of function must recognize the biological role of a molecule in the living context of a cell (or intracellular compartment) or the complete organism, and its role in a network of metabolic or control processes (Lan, Jansen and Gerstein, 2002; Lan, Montelione and Gerstein, 2003). There is a generic problem with all attempts to force functional classifications into a hierarchical format (see comments of Riley, 1998, and Shrager, 2003).

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