Editing Macroevolution (section)

=== Molecular macroevolution ===
Microevolution is facilitated by [[mutation]]s, the vast majority of which have no or very small effects on gene or protein function. For instance, the activity of an [[enzyme]] may be slightly changed or the stability of a protein slightly altered. However, occasionally mutations can dramatically change the structure and functions of protein. This may be called "molecular macroevolution".

[[File:PDB 2aj4 EBI.png|thumb|The metabolic enzyme [[galactokinase]] can be converted to a [[transcription factor]] (in [[Saccharomyces cerevisiae|yeast]]) by just a 2 amino-acid insertion.]]

'''Protein function'''. There are countless cases in which protein function is dramatically altered by mutations. For instance, a mutation in [[acetaldehyde dehydrogenase]] (EC:1.2.1.10) can change it to a [[4-hydroxy-2-oxovalerate aldolase|4-hydroxy-2-oxopentanoate pyruvate lyase]] (EC:4.1.3.39), i.e., a mutation that changes an [[enzyme]] from one to another [[Enzyme Commission number|EC]] class (there are only 7 main classes of enzymes).<ref>{{Cite journal |last1=Tyzack |first1=Jonathan D |last2=Furnham |first2=Nicholas |last3=Sillitoe |first3=Ian |last4=Orengo |first4=Christine M |last5=Thornton |first5=Janet M |date=2017-12-01 |title=Understanding enzyme function evolution from a computational perspective |journal=Current Opinion in Structural Biology |series=Protein–nucleic acid interactions • Catalysis and regulation |language=en |volume=47 |pages=131–139 |doi=10.1016/j.sbi.2017.08.003 |pmid=28892668 |issn=0959-440X|doi-access=free }}</ref> Another example is the conversion of a [[yeast]] [[galactokinase]] (Gal1) to a [[transcription factor]] (Gal3) which can be achieved by an insertion of only two amino acids.<ref>{{Cite journal |last1=Platt |first1=A. |last2=Ross |first2=H. C. |last3=Hankin |first3=S. |last4=Reece |first4=R. J. |date=2000-03-28 |title=The insertion of two amino acids into a transcriptional inducer converts it into a galactokinase |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=97 |issue=7 |pages=3154–3159 |doi=10.1073/pnas.97.7.3154 |issn=0027-8424 |pmc=16208 |pmid=10737789|bibcode=2000PNAS...97.3154P |doi-access=free }}</ref>

While some mutations may not change the molecular function of a protein significantly, their biological function may be dramatically changed. For instance, most brain receptors recognize specific neurotransmitters, but that specificity can easily be changed by mutations. This has been shown by [[acetylcholine receptor]]s that can be changed to [[serotonin]] or [[glycine receptor]]s which actually have very different functions. Their similar gene structure also indicates that they must have arisen from [[gene duplication]]s.<ref>{{Cite journal |last1=Uetz |first1=Peter |last2=Abdelatty |first2=Fawzy |last3=Villarroel |first3=Alfredo |last4=Rappold |first4=Gudrun |author-link4=Gudrun Rappold |last5=Weiss |first5=Birgit |last6=Koenen |first6=Michael |date=1994-02-21 |title=Organisation of the murine 5-HT 3 receptor gene and assignment tohuman chromosome 11 |journal=FEBS Letters |language=en |volume=339 |issue=3 |pages=302–306 |doi=10.1016/0014-5793(94)80435-4 |pmid=8112471 |s2cid=28979681 |doi-access=free|bibcode=1994FEBSL.339..302U }}</ref>

'''Protein structure'''. Although protein structures are highly conserved, sometimes one or a few mutations can dramatically change a protein. For instance, an [[Insulin-like growth factor-binding protein|IgG-binding]], 4<math>\beta</math>+<math>\alpha</math> fold can be transformed into an [[albumin]]-binding, 3-α fold via a single amino-acid mutation. This example also shows that such a transition can happen with neither function nor native structure being completely lost.<ref>{{Cite journal |last1=Alexander |first1=Patrick A. |last2=He |first2=Yanan |last3=Chen |first3=Yihong |last4=Orban |first4=John |last5=Bryan |first5=Philip N. |date=2009-12-15 |title=A minimal sequence code for switching protein structure and function |journal=Proceedings of the National Academy of Sciences |language=en |volume=106 |issue=50 |pages=21149–21154 |doi=10.1073/pnas.0906408106 |issn=0027-8424 |pmc=2779201 |pmid=19923431|doi-access=free }}</ref> In other words, even when multiple mutations are required to convert one protein or structure into another, the structure and function is at least partially retained in the intermediary sequences. Similarly, [[Protein domain|domains]] can be converted into other domains (and thus other functions). For instance, the structures of [[SH3 domain|SH3]] folds can evolve into [[OB-fold|OB folds]] which in turn can evolve into CLB folds.<ref>{{Cite journal |last1=Alvarez-Carreño |first1=Claudia |last2=Gupta |first2=Rohan J. |last3=Petrov |first3=Anton S. |last4=Williams |first4=Loren Dean |date=2022-12-27 |title=Creative destruction: New protein folds from old |journal=Proceedings of the National Academy of Sciences |language=en |volume=119 |issue=52 |pages=e2207897119 |doi=10.1073/pnas.2207897119 |doi-access=free |pmid=36534803 |pmc=9907106 |bibcode=2022PNAS..11907897A |s2cid=254907939 |issn=0027-8424}}</ref>