New roles of flavoproteins in molecular cell biology

The important role of flavoproteins in the oxidation–reduction reactions of primary metabolism has been known for many years. Electron transfer reactions in energy-yielding processes rely on flavin-dependent enzymes to convert a two-electron process into two one-electron events because the flavin group can accommodate either one or two electrons. There are hundreds of enzymes in which an FMN or FAD cofactor is required for the reduction (or oxidation) of a compound that is being synthesized or degraded. In most flavoproteins, the cofactor is strongly but noncovalently bound, but there are a large number of flavoproteins in which the flavin is covalently bound to the polypeptide chain. Several reasons have been put forward for covalent flavinylation. As indicated in the review by Heuts et al. recently published in this journal (include reference of review in issue 13), covalent binding can increase protein stability, ensure cofactor retention and/or induce a more positive redox potential of the cofactor. In recent years, new roles have being found for flavin-containing proteins because they are involved in regulatory processes. Photoreceptors act by sensing light in the regulation of circadian rhythms in animals and growth and development in plants. Among the blue-light photoreceptors, cryptochromes are interesting because they involved in the sensing of magnetic fields in several species. Another peculiarity is that they are closely related to the FAD-containing photolyase but lack the latter’s DNA repair activity. During the functioning of both proteins, paramagnetic radicals that can be studied using EPR techniques are generated. EPR and ENDOR techniques provide structural information about the environment of the flavin in the semiquinone state. The minireview by Schleicher et al. discusses recent studies in which modern EPR methods have been used to study these systems. A novel regulatory function has been described recently for a specific flavoprotein in humans. It is lysine-specific demethylase 1 (LSD1), an enzyme that eliminates the methyl groups in histones during the post-translational modification associated with gene activation. This interesting enzyme is only present in the nucleus of eukaryotes and is closely related to FAD-dependent amine oxidases. During evolution, the active site of LSD1 has come to be able to accommodate a long stretch of the histone protein and the enzyme has also acquired an extra domain called the ‘tower domain’ which allows it to target the large multiprotein nuclear complexes involved in chromatin remodeling and the regulation of gene transcription. This higher level of complexity, which adds an extra interest to the study of LSD1, is presented by Forneris et al. A third example of a regulatory role for a flavoprotein is described by Sollner and Macheroux. They describe the formation of a complex between a quinone reductase and the 20S proteasome in eukaryotes. Quinone reductases are FAD- or FMN-containing enzymes present in all kinds of organisms. Their function appears to be the reduction of quinones present in the cell, thereby avoiding the generation of harmful semiquinones. In recent years, a new role has been uncovered for quinone reductases as regulators of the proteasomal degradation of transcription factors and also of intrinsically unstructured proteins. Depending on the redox state of the flavin cofactor in the quinone reductase, the enzyme binds to the core particle of the proteasome and recruits certain transcription factors such as p53 and p73a, protecting them from degradation by the proteasome. The paradoxical protection of transcription factors by ‘hiding them near the lion’s den’ is a surprising twist to the complexity of cellular regulatory processes.