Moonlighting enzyme

As the sequences of complete genomes become available, the new challenge in biology is to assign functions to all the proteins whose sequence is known. We are now beginning to learn that there is not always a 1 to 1 correspondence between a protein and a function. Some proteins assemble with several others to carry out a function (see quaternary structure, modulator protein) and some proteins have multiple functions. The second class of proteins are known as multifunctional enzymes or moonlighting proteins.

Mechanism

• location in cell: the same protein may perform two different functions when located in different parts of a cell. PutA, a bacterial enzyme from Escheria coli acts as a pyrroline-5-carboxylate proline dehydrogenase when associated with the plasma membrane of a cell. However, when it is floating free in the cytoplasm, it has no enzymatic activity, but instead binds DNA and acts as a transcription factor, regulating gene expression.
• inside vs outside: Some proteins have a different function depending on whether they are retained within the cell or secreted out into the extracellular space. Phosphoglucose isomerase is a critical enzyme that catalyzes the second step of glycolysis. However, when secreted outside of the cell, it acts as the cytokine, neuroleukin, which causes B cells to mature into antibody-secreting cells. It also acts as a nerve growth-factor that promotes the survival of selected embryonic spinal neurons and sensory neurons.
• differential expression: If the same protein is expressed in different types of cells, it may carry out different roles. Neuropilin, when expressed in endothelial cells, can detect endothelial growth-factor and indicate if new blood cells need to be produced. However, if expressed in axons, it detects the ligand semaphorin III, which helps steer the axon in the proper direction during neural growth and development.
• oligomerization: defined as the process of assembling in groups. Some proteins function one way as a monomer (individually) and a different way as a multimer or oligomer. Glyceraldehyde-3-phosphate dehydrogenase is a glycolitic enzyme as a tetramer (assembled in sets of four). As a monomer, however, it behaves as a uracil-DNA glycosylase, repairing damaged DNA. Some proteins, instead of forming oligomers, form complexes (modulator proteins) which changes the activity of the catalytic protein.
• multiple binding sites: The multifunction of an enzyme can simply be a result of having several active sites on the same protein. The bacterial aspartate receptor, which functions in chemotaxis, but can also bind the sugar, maltose. The two chemicals, aspartate and maltose bind to different sites on the protein.

Evolution

The most straightforward answer is that organisms make use of what is already available. Many of the moonlighting enzymes are ones that are ubiquitously available in the cell, e.g. metabolic enzymes. If a new function is required, it is more likely that an existing enzyme will adapt to a new function rather than a new enzyme created de novo to accomodate this function. Glycolitic enzymes have been around since the earliest bacteria and ample time has passed to build these proteins into other cellular processes.

The advantage of moonlighting enzymes is straightforward ... the organism has to manufacture fewer proteins when one protein carries out several functions. This means less materials consumed to make proteins, and less energy spent replicating DNA. This could save a great deal of energy during growth and replication.

see also evolution of metabolic pathways