# Phosphomimetics
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{{Short description|Amino acid substitutions that mimic a phosphorylated protein}}
thumb|Example of a phosphomimetic substitution: aspartic acid compared to phospho-serine
'''Phosphomimetics''' are [amino acid](/source/amino_acid) substitutions that mimic a [phosphorylated protein](/source/Chemical_Biology), thereby activating (or deactivating) the protein. Within cells, proteins are commonly modified at [serine](/source/serine), [tyrosine](/source/tyrosine) and [threonine](/source/threonine) amino acids by adding a [phosphate](/source/phosphate) group. [Phosphorylation](/source/Phosphorylation) is a common mode of activating or deactivating a protein as a form of regulation. However some non-phosphorylated amino acids appear chemically similar to phosphorylated amino acids. Therefore, by replacing an amino acid, the protein may maintain a higher level of activity. For example, [aspartic acid](/source/aspartic_acid) can be considered chemically similar to phospho-serine, due to it also carrying a negative charge. Therefore, when an aspartic acid replaces a [serine](/source/serine), it is a phosphomimetic of phospho-serine and can imitate the protein always in its phosphorylated form. However, differences between the phosphomimetic compound and the phosphorylated residue, notably differences in [Ramachandran distributions](/source/Ramachandran_plot),[{{Cite journal |last1=He |first1=Erbin |last2=Yan |first2=Guanghui |last3=Zhang |first3=Jian |last4=Wang |first4=Jun |last5=Li |first5=Wenfei |date=March 2016 |title=Effects of phosphorylation on the intrinsic propensity of backbone conformations of serine/threonine |journal=Journal of Biological Physics |language=en |volume=42 |issue=2 |pages=247–258 |doi=10.1007/s10867-015-9405-0 |issn=0092-0606 |pmc=4788628 |pmid=26759163}}] charge states[{{Cite journal |last1=Platzer |first1=Gerald |last2=Okon |first2=Mark |last3=McIntosh |first3=Lawrence P. |date=November 2014 |title=pH-dependent random coil 1H, 13C, and 15N chemical shifts of the ionizable amino acids: a guide for protein pK a measurements |url=http://link.springer.com/10.1007/s10858-014-9862-y |journal=Journal of Biomolecular NMR |language=en |volume=60 |issue=2–3 |pages=109–129 |doi=10.1007/s10858-014-9862-y |pmid=25239571 |issn=0925-2738|url-access=subscription }}] and size, can alter the protein sufficiently to result in significant differences in behavior.[{{Cite journal |last1=Paleologou |first1=Katerina E. |last2=Schmid |first2=Adrian W. |last3=Rospigliosi |first3=Carla C. |last4=Kim |first4=Hai-Young |last5=Lamberto |first5=Gonzalo R. |last6=Fredenburg |first6=Ross A. |last7=Lansbury |first7=Peter T. |last8=Fernandez |first8=Claudio O. |last9=Eliezer |first9=David |last10=Zweckstetter |first10=Markus |last11=Lashuel |first11=Hilal A. |date=June 2008 |title=Phosphorylation at Ser-129 but Not the Phosphomimics S129E/D Inhibits the Fibrillation of α-Synuclein |journal=Journal of Biological Chemistry |language=en |volume=283 |issue=24 |pages=16895–16905 |doi=10.1074/jbc.M800747200 |doi-access=free |pmc=2423264 |pmid=18343814}}] [Phosphonate](/source/Phosphonate)-based compounds have been used as [phosphotyrosine](/source/Tyrosine) analogues, as they are less enzyme labile and are physiologically more stable.[{{cite journal |author=Nikolai Makukhin |author2=Alessio Ciulli | title = Recent advances in synthetic and medicinal chemistry of phosphotyrosine and phosphonate-based phosphotyrosine analogues | journal = RSC Medicinal Chemistry |date=2020 | volume = 12 | issue = 1 | pages = 8–23 | doi=10.1039/D0MD00272K | pmid = 34041480 | pmc=8130623 | doi-access = free }}]
== Applications ==
This chemical similarity can be exploited in [cancer](/source/cancer), where a protein may mutate into an "always on" (constitutively active) state. A mutation may occur to replace a [tyrosine](/source/tyrosine) (which needs to be phosphorylated in order to activate the protein) with an aspartic acid (which would not need to be phosphorylated). In a laboratory setting, the use of [recombinant protein](/source/recombinant_protein)s to artificially introduce phosphomimetics is a common tool for studying phosphorylation and protein activation. For example, the [IRF3](/source/IRF3) protein must be phosphorylated for its normal activity (transcription of its target genes, like [IFNβ](/source/Interferon)), but when serine amino acid residues were mutated to aspartic acid, the activity increased 90-fold.[{{cite journal |vauthors=Hiscott J, Pitha P, Genin P, Nguyen H, Heylbroeck C, Mamane Y, Algarte M, Lin R | title = Triggering the interferon response: the role of IRF-3 transcription factor. | journal = J Interferon Cytokine Res| volume = 19 | issue = 1 | pages = 1–13 |date=Jan 1999 | pmid = 10048763 | doi = 10.1089/107999099314360 }}] Phosphomimetics are commonly used in a [gain of function](/source/genetic_engineering) experiment with respect to phosphorylation. For example, aspartate mutants were successfully used to probe the biological function of the phosphorylation of a [threonine](/source/threonine) residue of a [ribosomal protein](/source/ribosomal_protein) both ''in vivo''[{{cite journal |author=Ian Martin |author2=Jungwoo Wren Kim |author3=Byoung Dae Lee |author4=Ho Chul Kang |author5=Jin-Chong Xu |author6=Hao Jia |author7=Jeannette Stankowski |author8=Min-Sik Kim |author9=Jun Zhong |author10=Manoj Kumar |author11=Shaida A Andrabi |author12=Yulan Xiong |author13=Dennis W Dickson |author14=Zbigniew K Wszolek |author15=Akhilesh Pandey |author16=Ted M Dawson |author17=Valina L Dawson | title = Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease | journal = Cell | volume = 157 | issue = 2 | pages = 472–485 |date=2014 | pmid = 24725412 | doi = 10.1016/j.cell.2014.01.064|pmc=4040530 | doi-access = free }}] and ''in vitro''[{{cite journal |author=Danilo Correddu |author2=Nabangshu Sharma |author3=Simranjeet Kaur |author4=Kyriakos G Varnava |author5=Naasson M Mbenza |author6=Vijayalekshmi Sarojini |author7=Ivanhoe K H Leung | title = An investigation into the effect of ribosomal protein S15 phosphorylation on its intermolecular interactions by using phosphomimetic mutant | journal = Chem. Commun. | volume = 56 | issue = 57 | pages = 7857–7860 |date=2020 | pmid = 32583822 | doi = 10.1039/d0cc01618g | s2cid = 220058870 |hdl=2292/52389 |hdl-access=free }}] to investigate a [gain-of-function mutation](/source/Mutation) on a [kinase](/source/kinase) that is related to [Parkinson's disease](/source/Parkinson's_disease). Phosphomimetics were also used to investigate the therapeutic potential of proteins or peptides. For example, phosphomimetic mutants (using [glutamate](/source/glutamate) to mimic serine phosphorylation) have been used to demonstrate that the phosphorylated [glycoprotein](/source/glycoprotein)s may have stronger anti-[melanoma](/source/melanoma) effects that the wildtype protein.[{{cite journal |author=Ye Feng |author2=Wenjing Bao |author3=Yanli Luo |author4=Ling Tian |author5=Xiafang Chen |author6=Miaoying Yi |author7=Hui Xiong |author8=Qian Huang | title =Phosphomimetic mutants of pigment epithelium-derived factor with enhanced anti-choroidal melanoma cell activity in vitro and in vivo | journal = Invest. Ophthalmol. Vis. Sci. | volume = 53 | issue = 11 | pages = 6793–6802 |date=2012 | pmid =22952124 | doi = 10.1167/iovs.12-10326 | doi-access = free }}] This approach is in particularly useful as up to three serine residues can be phosphoylated on the said protein,