Operon

The Discovery of Operons

French scientists Jacques Monod and François Jacob first coined the term "operon" in a short paper published in 1960 in the Proceedings of the French Academy of Sciences. They elaborated the concept of the operon in several papers that appeared in 1961, based on their studies on the lac genes (genes for the metabolism of lactose sugar) of the bacterium Escherichia coli and the genes of bacteriophage lambda. Monod and Jacob received the Nobel Prize in 1985 for this work.

Typical Features of Operons

The genes of an operon are usually functionally related. Genes are the basic unit of biological information, and consist of specific segments of deoxyribonucleic acid (DNA). The segments of DNA that constitute a gene consist of distinctive sets of nucleotide pairs located in a discrete region of a chromosome that encodes a particular protein. Within an operon, the genes encode proteins that execute related functions. For example, the five genes of the tryptophan (trp) operon in E. coli each encode one of the enzymes necessary for the biosynthesis of the amino acid tryptophan from a metabolite called chorismate. This condition is mimicked in many bacteria.

Exceptions do occur; the genes of some operons may lack an obvious functional relationship. For example one operon in E. coli contains one gene that encodes a ribosomal protein S21 (rpsU), another that encodes DNA primase (dnaG), and one that encodes the sigma subunit of RNA polymerase (rpoD). The protein products of these genes are all involved in starting up the synthesis of macromolecules, but beyond that they have no obvious functional relationships to one another. Nonetheless, the clustering of these genes and their common regulation qualify them to be treated as elements of a single operon.

Another common feature of operons is that their genes are clustered on the bacterial chromosome. This chromosome is a large circular molecule of DNA. The genes of an operon are arranged in a consecutive and linear fashion at a specific location on the bacterial chromosome.

In the case of the lactose utilization (lac) operon of E. coli, three genes necessary for the successful utilization of the disaccharide lactose, a common sugar found in milk, are arranged in a linear fashion on the chromosome (see Figure 1). The lacZ gene, which encodes the lactose-degrading enzyme, β-galactosidase, is directly followed by the lacY gene, which encodes a membrane protein, called lactose permease, that allows the entry of lactose into the cell. The lacY gene is immediately followed by the lacA gene, which encodes the thiogalactoside acetyltransferase enzyme that detoxifies lactose-related compounds that might be toxic to the cell. The linear arrangement of these functionally related genes is a hallmark of an operon. The arrangement is significant because the proteins made from these genes will all be easily turned on in concert, so that lactose metabolism proceeds rapidly and efficiently.

Other Typical Characteristics

The clustered genes of the operon typically share a common promoter and a common regulatory region, called an operator. Gene expression requires the enzyme RNA polymerase to transcribe (synthesize an RNA copy of) the gene. This RNA copy is called a messenger RNA (mRNA), which is translated by ribosomes to produce the protein encoded by the gene. In all genes, RNA polymerase begins transcription at a specific site or sequence called the promoter (designated "P" in Figure 1). The genes in an operon usually share a common promoter from which the genes of the operon are transcribed.

Operons almost always contain a common promoter region, but not all operons contain only a single promoter. For example the E. coli operon for galactose utilization (gal) contains two promoters. One of these promoters is active in the presence of glucose, and the other is not (both glucose and galactose are sugars). Some operons, like the trp and isoleucine-valine (ilv) operons, both from E. coli, also have internal promoters that allow the expression of some but not all of the genes in the operon. (Isoleucine and valine are amino acids.)

Operons also have one or more control regions, called operators, that mediate the expression of the genes in the operon (the operator is designated "O" in Figure 1). Like a promoter, an operator is a site on the DNA, but it does not bind with RNA polymerase. Operators function in one of two ways. They can contain DNA sequences that specifically bind particular proteins. Once bound onto DNA, these proteins can prevent the expression of the operon by interfering with the action of RNA polymerase, as in the case of the lac repressor. Other proteins bound on other operons can greatly enhance the expression of the operon, as in the case of the AraC protein. Operators can thus prevent or facilitate gene expression.

Instead of acting as target sites for DNA-binding proteins, operators also act as the sites of regulation by attenuation. Amino acid biosynthesis operons such as trp are usually regulated by attenuation. In such operons the operator provides both a start site for transcription and a ribosome-binding site for the synthesis of a short leader peptide. Through a clever mechanism, the presence of sufficient amino acid in the cell causes the ribosome to disrupt transcription. When the supply of the amino acid is low, transcription of the operon continues without interruption. In this way, if the proteins coded for by the operon genes are needed to synthesize amino acids, then early transcriptional termination does not occur. If they are not needed, because the amino acid is already present, then early termination ensues. This prevents the wasteful production of unnecessary proteins.

The genes of an operon also show a common mode of regulation. The clustering of the genes of an operon and the related functions of these genes requires a mode of regulation that equally affects all the genes of the operon. In the case of the lac operon of E. coli, the product of the lacI gene is a DNA-binding protein that specifically binds to the lac operator and prevents RNA polymerase from initiating transcription of the lactose utilization genes from the promoter. Therefore, in the absence of lactose, the lactose utilization genes are only expressed at a very low basal level (see Figure 2A). This low level of expression allows synthesis of a few lactose permease molecules, which permit the entry of lactose into the cell when lactose is present, and a few β-galactosidase molecules, which metabolize lactose or convert it to allolactose.

Allolactose is the inducer of the lac operon, acting as a signal that lactose is present. Allolactose binds to the repressor protein, changing its shape in such a way that the repressor can no longer bind to the operator. This allows RNA polymerase to effectively initiate transcription from the lac promoter (see Figure 2B).

Transcription of an operon generates an mRNA transcript of all the genes contained within the operon. Ribosomes can translate this single mRNA to generate several distinct proteins. In the case of the lac operon, transcription produces an mRNA molecule that is translated by ribosomes to generate β-galactosidase, lactose permease, and thiogalactoside acetyltransferase. Messenger RNA molecules that encode more than one gene are called polycistronic mRNAs. The common regulation mechanism determines when each polycistronic mRNA is synthesized. This is the main means by which operons commonly regulate the expression of one or more functionally regulated genes.

SEE ALSO DNA; ESCHERICHIA COLI (E. COLI BACTERIUM); GENE; GENE EXPRESSION: OVERVIEW OF CONTROL; PROTEINS.

Michael Buratovich

Bibliography

Hartwell, Leland, et al. Genetics: From Genes to Genomes. Berkeley: McGraw-Hill, 2000.

Miller, Jeffrey H., and Reznikoff, William S., eds. Operon, 2nd ed. Cold Spring Harbor, NY: Cold Spring Harbor Press, 1980.