The DNA molecule is often termed the blueprint of life. However, you cannot cook using the blueprint of a kitchen or bathe in the blueprint of a bathroom. Of the two major products of the gene (proteins and miscellaneous RNAs), it is the protein that is the main functional unit of biology. A combinatorial association of 20 amino acids in linear chains of up to 30 000 residues generates, or can generate in theory, many more proteins than there are stars in our universe or, indeed, atoms in our universe. The protein molecule can be chemically active, in the form of an enzyme, whose catalytic effect can speed up chemical reactions by a thousand‐ to a billion‐fold. It can be a structural component, acting as a tissue support or allowing the transmission of force. It can function as a binding molecule, acting to transport other molecules or atoms, or act as a receptor binding its ligand to transmit information into the cell. Proteins are vitally important for life, and this is clearly indicated by the number of genetic diseases whose symptoms are due to altered protein sequences. The classic example of this is sickle cell disease, due to a single amino acid substitution in hemoglobin, resulting in a protein that aggregates when deoxygenated, causing massive structural changes in circulating erythrocytes. The function of proteins can be explained by the evolution in the protein of a specific interaction between amino acids to generate what is termed an active site/binding site.

The central dogma, formulated by Francis Crick (and following on from the work of Beadle and Tatum), suggested the direction of information flow in biology was from DNA to RNA to protein. This is now known to be wrong in several ways. Not stated in the central dogma, but generally taken for granted, was that each protein product of the gene had one single biological function. Like all good Popperian hypotheses, this one‐protein‐one‐function hypothesis was falsified by the first example of a protein exhibiting two functions. However, this finding failed to make much of an impact on science and it was only in the 1980s, through the studies of Joram Piatigorsky on the composition of the lenses of invertebrates and vertebrates, that it came to the attention of the scientific community that many of the proteins in the lens were known metabolic enzymes and molecular chaperones. Piatigorsky named this phenomenon, gene sharing, but the term was overwhelmed by a welter of other similar terms from molecular biology and largely became lost to view. In addition, it can be argued that the transparency of a protein is not really a functional property, but is a bulk physical property of these molecules. So it was not until the 1990s that additional examples of proteins exhibiting more than one function were identified and another term to describe this phenomenon was introduced. Connie Jeffery, from the University of Chicago, introduced the term protein moonlighting in 1999 for the phenomenon of proteins having more than one unique biological function. Since the introduction of the term, protein moonlighting, a slow trickle of serendipitous discoveries of moonlighting proteins has been made such that, at the time of writing, over 200 examples of such proteins have been made. While this is a small number of examples, it is possibly only the tip of the iceberg that is the population of moonlighting proteins in biology.

Protein moonlighting has only come to prominence in the last 15 years. Although only a small number of protein families have been found to moonlight, the consequences of such additional activities are already known to be of both biological and pathological/medical significance. Moonlighting proteins are known to be involved in human diseases such as atherosclerosis and cancer and there is rapidly emerging evidence for a major role for protein moonlighting in the infectious diseases. Protein moonlighting has potential consequences for various branches of biology. The most obvious is the field of protein evolution. In moonlighting proteins not one but two or more active sites have evolved. This calls into question our current models of protein evolution and generates a range of questions as to the evolutionary mechanisms involved. Further, as it is emerging that moonlighting protein homologues do not necessarily share specific moonlighting activities, the level of evolutionary complexity in generating biologically active sites seems much greater than was previously thought. Another area impacted by protein moonlighting is the emerging field of systems biology. The complexity of cellular systems with their multitudes of interacting networks of proteins is currently predicated on each protein having one function. However, if a sizable proportion of proteins moonlight, then this will dramatically increase cellular network complexity.

This book brings together a biochemist (Henderson), an evolutionary biologist (Fares), and a protein bioinformaticist (Martin) who have had a long‐term interest in protein moonlighting. The discussion covers all aspects of the phenomenon of protein moonlighting from its evolution to structural biology and on to the biological and medical consequences of its occurrence. The book should be of interest to the widest range of biomedical scientists.