Deoxyhypusine synthase

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(New page: <StructureSection load='2emt' size='340' side='right' caption='Mouse radixin FERM domain (green) complex with N-terminal peptide of the adhesion molecule PSGL-1 (yellow) (PDB code 2emt...)
Current revision (13:03, 11 February 2021) (edit) (undo)
 
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<StructureSection load='2emt' size='340' side='right' caption='Mouse radixin FERM domain (green) complex with N-terminal peptide of the adhesion molecule PSGL-1 (yellow) (PDB code [[2emt]])' scene='77/777076/Cv/1'>
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<StructureSection load='6xxk' size='340' side='right' caption='Human deoxypusine synthase with mercaptocysteine complex with spermidine, ethylene glycol, formate, acetate, mercaptoethanol, MPD (PDB code [[6xxk]])' scene='87/874448/Cv/7'>
== Function ==
== Function ==
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'''Deoxyhypusine synthase''' (DHS) plays an important role in promoting cell migration by regulating Rac-1-mediated epithelial polarity and formation of adherens junctions through Rac guanine nucleotide exchange factors<ref>PMID:22467863</ref>. Rdx is part of the ERM (Ezrin/Radixin/Moesin) which is linked to cell shape change. Phosphorylation of the C-terminal Thr residues of ERM inhibits cell adhesion and induces formation of spherical cell shape<ref>PMID:26555866</ref>.
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'''Deoxyhypusine synthase''' (DHS) catalyzes the biosynthesis of deoxyhypusine by transfer of 4-aminobutyl moiety of spermidine to a specific Lys residue of initiation factor 4D<ref>PMID:2108161</ref>. Hypusine is formed post-translationally and is found in translation initiation factor 5A (elf5A).
== Disease ==
== Disease ==
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Rdx deficiency causes increase in bilirubin in serum, a phenotype similar to that of Dubin-Johnson syndrome in human<ref>PMID:12068294</ref>.
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Mutations in DHS result in reduced enzyme activity that limit the hypusination of elf5A which is associated with neurodevelopmental disorder<ref>PMID:30661771</ref>.
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==Relevance ==
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Inhibition of DHS may provide a strategy for reducing diabetogenic cells and preserving β cell function in type 1 diabetes<ref>PMID:24196968</ref>.
== Structural highlights ==
== Structural highlights ==
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The <scene name='77/777076/Cv/3'>hydrophobic groove of the FERM domain of Rdx binds the N-terminal peptide of the adhesion molecule</scene> hydrophobic groove of the FERM domain of Rdx binds the N-terminal peptide of the adhesion molecule P-selectin glycoprotein ligand 1 with multiple hydrogen bonds<ref>PMID:18706570</ref>. {{Template:ColorKey_Hydrophobic}}, {{Template:ColorKey_Polar}}
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The Biological assembly of Human deoxypusine synthase is <scene name='87/874448/Cv/6'>homotetramer</scene> (PDB code [[6xxk]]). <scene name='87/874448/Cv/5'>The complex between DHS and its substrate spermidine</scene> shows the binding in the active site with spermidine forming hydrogen bonds to DHS with its 2 terminal amino groups <ref>PMID:32235505</ref>. Water molecules are shown as red spheres.
</StructureSection>
</StructureSection>
== 3D Structures of deoxyhypusine synthase ==
== 3D Structures of deoxyhypusine synthase ==

Current revision

Human deoxypusine synthase with mercaptocysteine complex with spermidine, ethylene glycol, formate, acetate, mercaptoethanol, MPD (PDB code 6xxk)

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3D Structures of deoxyhypusine synthase

Updated on 11-February-2021

6xxh – hDHS – human
1dhs, 1rlz, 1roz, 6dft, 6xxi – hDHS + NAD
6xxm – hDHS + putrescine
6pgr, 6wkz, 6wl6 – hDHS + inhibitor
6xxl – hDHS + spermine
6xxk – hDHS + spermidine
6xxj – hDHS + NAD + spermidine
1rqd, 6prv – hDHS + NAD + inhibitor
7cmc – DHS + NAD - Pyrococcus horikishii
6w3z – DHS + NAD – Brugia malayi


References

  1. ↑ Wolff EC, Park MH, Folk JE. Cleavage of spermidine as the first step in deoxyhypusine synthesis. The role of NAD. J Biol Chem. 1990 Mar 25;265(9):4793-9. PMID:2108161
  2. ↑ Ganapathi M, Padgett LR, Yamada K, Devinsky O, Willaert R, Person R, Au PB, Tagoe J, McDonald M, Karlowicz D, Wolf B, Lee J, Shen Y, Okur V, Deng L, LeDuc CA, Wang J, Hanner A, Mirmira RG, Park MH, Mastracci TL, Chung WK. Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder. Am J Hum Genet. 2019 Feb 7;104(2):287-298. doi: 10.1016/j.ajhg.2018.12.017. Epub , 2019 Jan 17. PMID:30661771 doi:http://dx.doi.org/10.1016/j.ajhg.2018.12.017
  3. ↑ Colvin SC, Maier B, Morris DL, Tersey SA, Mirmira RG. Deoxyhypusine synthase promotes differentiation and proliferation of T helper type 1 (Th1) cells in autoimmune diabetes. J Biol Chem. 2013 Dec 20;288(51):36226-35. doi: 10.1074/jbc.M113.473942. Epub, 2013 Nov 6. PMID:24196968 doi:http://dx.doi.org/10.1074/jbc.M113.473942
  4. ↑ Wator E, Wilk P, Grudnik P. Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase. Biomolecules. 2020 Mar 30;10(4). pii: biom10040522. doi: 10.3390/biom10040522. PMID:32235505 doi:http://dx.doi.org/10.3390/biom10040522

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