Protein of the Month

May 2007






Molecule of the Month: Aconitase




ExPASy Protein Spotlight



By Jennifer McDowall


            The concept of a gene encoding a specific enzyme first arose with Garrod in 1909, an English physician studying the inherited condition alkaptonuria.  Later in 1941, the American geneticists Beadle and Tatum proposed the ‘one gene, one enzyme’ hypothesis, which was later adapted to ‘one gene, one polypeptide’ as some proteins are composed of different polypeptide chains, and not all are enzymes. 

However, today we realise that one gene does not necessarily encode one polypeptide with a single function.  Eukaryotic genomes employ various methods of increasing protein functionality without being burdened with ever expanding genome size - hence the lower number of genes found in the human genome (20,000-25,000) than were initially predicted. 

One means of increasing proteome complexity is via alternative splicing.  By using different combinations of exons, a single gene can yield different polypeptide products, which could differ in their substrate targeting, tissue-specificity, or developmental expression.  The prevalence of alternatively spliced genes has been shown to increase with increased organism complexity.

Another option involves the evolution of multi-functional proteins, which can arise in different ways:

·        Catalytic promiscuity, where an enzyme can use the same active site to catalyse secondary reactions.

·        Bifunctional enzymes that catalyse two independent reactions at separate active sites.

·        Moonlighting proteins that are able to perform multiple, independent functions, but which do not arise through gene fusion.

Multi-functional proteins enable an organism to reduce its genome size, saving energy in growth and reproduction.  In addition, they can help coordinate related cellular activities in an otherwise complex environment, or provide a switch point in a metabolic or signalling pathway so a cell can switch between different functions in response to cellular conditions.

            Moonlighting proteins are of special interest, arising from existing proteins by recruiting existing binding sites for new functions, or by modifying unused regions for a new purpose.  These proteins are usually metabolic enzymes, which in addition to catalysis can perform a second, independent, non-catalytic function that ranges from signal transduction (transcriptional regulation, apoptosis), growth and motility (tumour suppression, growth factors, DNA repair), to structural functions (lens crystallins).  Some can perform both an enzymatic and a secondary function simultaneously, while others switch between two functions.  However, not all moonlighting proteins are enzymes; receptors, transmembrane channels, chaperones and ribosomal proteins can also exhibit moonlighting activities.

            Several moonlighting proteins have been identified in eukaryotes, especially among familiar enzymes.  For instance, 7 out of 10 enzymes in glycolysis, and at least 7 of the 8 enzyme in the tricarboxylic acid cycle have moonlighting activities.  One such enzyme is aconitase.


Next:  Aconitase, a moonlighting enzyme