In praise of erroneous hypotheses

• The induction mechanism of nitrate utilisation is a paradigmatic system in fungi.
• The nitrate reductase protein was proposed to act as a co-repressor in this system.
• This “autogenous regulation hypothesis” has been proven erroneous.
• This hypothesis has been, nevertheless, of heuristic and evolutionary importance.
• The origin of transcription regulatory proteins from enzymes is discussed.

In the sixties Cove and Pateman discovered that mutants of Aspergillus nidulans lacking nitrate reductase activity were constitutive for the expression of genes induced by nitrate and dependent on the transcription factor NirA. They proposed that the nitrate protein acted as a repressor, preventing the transcription factor activity of NirA. Nitrate-mediated regulation behaved similarly in other organisms. This “autogenous regulation hypothesis” has recently shown to be erroneous, in the very organism for which it was first proposed. Nevertheless this erroneous hypothesis have led to a thorough dissection of the process of regulation of nitrate assimilation and more importantly to a hypothesis bearing on the origin of metabolite-responsive transcription factors. In this article I discuss the heuristic value and evolutionary importance of autogenous regulation.