Editing Rossmann fold (section)

== Evolution ==

=== Rossman and Rossmannoids ===
The evolutionary relationship between the Rossmann fold and Rossmann-like folds is unclear. These folds are referred to as Rossmannoids. It has been hypothesized that all these folds, including a Rossmann fold originated from a single common ancestral fold, that had nucleotide binding capabilities, in addition to non-specific catalytic activity.<ref name="Kessel_2010" />

However, an analysis of the PDB finds evidence of [[convergent evolution]]<ref name=Medvedev_2019>{{cite journal | vauthors = Medvedev KE, Kinch LN, Schaeffer RD, Grishin NV | title = Functional analysis of Rossmann-like domains reveals convergent evolution of topology and reaction pathways | journal = PLOS Computational Biology | volume = 15 | issue = 12 | pages = e1007569 | date = December 2019 | pmid = 31869345 | pmc = 6957218 | doi = 10.1371/journal.pcbi.1007569 | doi-access = free | bibcode = 2019PLSCB..15E7569M }}</ref> with 156 separate H-groups of demonstrable homology, from which 123 X-groups of probable homology can be found. The groups have been integrated into [[ECOD]].<ref name=Med>{{cite journal | vauthors = Medvedev KE, Kinch LN, Dustin Schaeffer R, Pei J, Grishin NV | title = A Fifth of the Protein World: Rossmann-like Proteins as an Evolutionarily Successful Structural unit | journal = Journal of Molecular Biology | volume = 433 | issue = 4 | pages = 166788 | date = February 2021 | pmid = 33387532 | pmc = 7870570 | doi = 10.1016/j.jmb.2020.166788 }}<br />{{cite web | vauthors = Medvedev KE, etal |title=Rossmann-fold project |url=http://prodata.swmed.edu/rossmann_fold/ |work = Grishin Lab | publisher = UT Southwestern Medical Center }}</ref>

=== Conventional Rossman group ===
Phylogenetic analysis of the NADP binding enzyme [[adrenodoxin reductase]] revealed that from prokaryotes, through metazoa and up to primates the sequence motif difference from that of most FAD and NAD-binding sites is strictly conserved.<ref name="Hanukoglu_2017">{{cite journal | vauthors = Hanukoglu I | title = Conservation of the Enzyme-Coenzyme Interfaces in FAD and NADP Binding Adrenodoxin Reductase-A Ubiquitous Enzyme | journal = Journal of Molecular Evolution | volume = 85 | issue= 5 | pages= 205–218 | year= 2017 | pmid= 29177972 | doi= 10.1007/s00239-017-9821-9 | bibcode = 2017JMolE..85..205H | s2cid = 7120148 }}</ref>

In many articles and textbooks, a Rossmann fold is defined as a strict repeated series of βαβ structure. Yet, comprehensive examination of the Rossmann folds in many NAD(P) and FAD binding sites revealed that only the first βα structure is strictly conserved. In some enzymes, there may be many loops and several helices (i.e., not a single helix) between the beta strands that form the beta-sheet.<ref name="Hanukoglu_2015" /> These enzymes have a common origin indicated by conserved sequence and structural features, according to Hanukoglu.<ref name="Hanukoglu_2017" />

The result by Hanukoglu (2017) is corroborated by Medvedev et al. (2020), in the form of an ECOD "H-group" called "[http://prodata.swmed.edu/ecod/complete/tree?id=2003.1 Rossmann-related]". Even within this group, ECOD describes a wide range of non-nucleotide activities.<ref name=Med/>