6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase

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(New page: <StructureSection load='3udv' size='340' side='right' caption='Structure of E. coli HPPK complex with inhibitor (PDB code 3udv).' scene=''> == Function == '''6-hydroxymethyl-7,8-dih...)
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<StructureSection load='3udv' size='400' side='right' caption='Structure of E. coli HPPK complex with inhibitor (green) (PDB code [[3udv]]).' scene='59/593854/Cv/1' pspeed='8'>
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__TOC__
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== Function ==
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<StructureSection load='3udv' size='340' side='right' caption='Structure of E. coli HPPK complex with inhibitor (PDB code [[3udv]]).' scene=''>
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'''6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase''' (HPPK) or '''2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase''' is a prokaryotic enzyme which is part of the folate synthesis pathway. HPPK catalyzes the attachment of pyrophosphate from ATP to 6-hydroxymethyl-7,8-dihydropterin (HMDP) to form
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6-hydroxymethyl-7,8-dihydropteridine pyrophosphate. Mg+2 ion is important for binding ATP and HMDP.<ref>PMID:10378268</ref>
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== Function ==
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The'' Plasmodium'' parasites encode a protein fused of '''HPPK''' and '''dihydroperoate synthase''' ('''HPPK-DHPS''') which catalyse reaction in the folate biosynthesis pathway<ref>PMID:30104413</ref>.
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'''6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase''' (HPPK) is a prokaryotic enzyme which is part of the folate synthesis pathway. HPPK catalyzes the attachment of pyrophosphate to 6-hydroxymethyl-7,8-dihydropterin to form
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The reaction catalyzed by HPPK involves the transfer of a pyrophosphate group from ATP to HMDP, leading to the formation of HMDPTP and ADP. This phosphorylation step is essential for subsequent reactions in the folate biosynthesis pathway, leading to the production of THF.
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6-hydroxymethyl-7,8-dihydropteridine pyrophosphate. HPPK is inhibited by a variety of antimicrobial agents like trimethoprim and sulfonamides.
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== Disease ==
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== Relevance ==
== Relevance ==
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== Structural highlights ==
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HPPK is a potential target for antimicrobial drugs like trimethoprim and sulfonamides.
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==3D structures of HPPK==
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Deficiencies or dysregulation of HPPK can disrupt the folate biosynthesis pathway and lead to impaired cellular processes dependent on THF. Genetic mutations affecting HPPK function have been associated with rare metabolic disorders, such as dihydropteridine reductase deficiency, which is characterized by impaired production of THF and neurotransmitters.
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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Understanding the structure and function of HPPK has provided insights into the folate biosynthesis pathway and its role in cellular metabolism. Moreover, HPPK has been considered as a potential target for the development of antimicrobial agents, as the folate biosynthesis pathway is essential for the survival and proliferation of certain bacteria, making HPPK an attractive candidate for drug discovery.
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[[1hka]], [[1eq0]] – EcHPPK – ''Escherichia coli''<br />
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In summary, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is an enzyme involved in the biosynthesis of tetrahydrofolate (THF). It catalyzes the phosphorylation of 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (HMDP) to produce 6-hydroxymethyl-7,8-dihydropterin triphosphate (HMDPTP), an intermediate in the folate biosynthesis pathway. HPPK plays a critical role in regulating THF levels and is of biological and potential therapeutic importance.
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[[1g4c]], [[1im6]], [[1kbr]], [[1rtz]], [[1tmj]], [[3hcx]], [[3hsd]], [[3hsj]], [[3hsz]], [[3ili]], [[3ill]], [[3kue]], [[3kug]] – EcHPPK (mutant) <br />
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[[2f63]], [[2f65]] – EcHPPK - NMR <br />
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===HPPK binary complex===
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== Structural highlights ==
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[[1cbk]] – HPPK + dihydro-dimethyl-6-hydroxypterin – ''Haemophilus influenza''<br />
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Three loop regions surround the HPPK active site. Upon binding of ATP, the <scene name='59/593854/Cv/2'>flexible loops</scene> region (purple) changes its conformation and enables the binding of HMDP. <scene name='59/593854/Cv/6'>Active site</scene>. Water molecules are shown as red spheres.
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[[1eqm]] – EcHPPK + ADP <br />
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[[1ex8]] – EcHPPK + adenosine-tetraphosphate-methyl-dihydropterin <br />
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[[1rb0]] – EcHPPK + 6-hydroxymethylpterin-diphosphate <br />
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[[3hd1]], [[3hsg]], [[3ht0]], [[3ilj]], [[3kuh]] – EcHPPK (mutant) + methyleneadenosine-triphosphate <br />
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[[3ud5]], [[3ude]], [[3udv]], [[4f7v]] – EcHPPK + inhibitor <br />
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[[3qbc]] – HPPK + inhibitor – ''Staphylococcus aureus''<br />
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===HPPK ternary complex===
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==3D structures of HPPK==
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[[HPPK 3D structures]]
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[[1ru2]], [[1tmm]] – EcHPPK (mutant) + methyleneadenosine-triphosphate + 6-hydroxymethylpterin <br />
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</StructureSection>
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[[1dy3]] – EcHPPK (mutant) + ATP + pteridine derivative <br />
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[[3ip0]] – EcHPPK + methyleneadenosine-triphosphate + pteridine derivative <br />
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[[1f9h]], [[1hq2]], [[1q0n]], [[1ru1]], [[3ilo]] – EcHPPK (mutant) + methyleneadenosine-triphosphate + pteridine derivative <br />
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[[3hd2]] – EcHPPK (mutant) + methyleneadenosine-triphosphate + pterine <br />
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[[4m5g]], [[4m5h]], [[4m5i]], [[4m5j]], [[4m5k]], [[4m5l]], [[4m5m]], [[4m5n]] – EcHPPK + methyleneadenosine-triphosphate + inhibitor <br />
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[[1rao]] – EcHPPK (mutant) + AMP + 6-hydroxymethylpterin-diphosphate <br />
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[[2qx0]] – HPPK + methyleneadenosine-triphosphate + pteridine derivative – ''Yersinia pestis''<br />
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Current revision

Structure of E. coli HPPK complex with inhibitor (green) (PDB code 3udv).

Drag the structure with the mouse to rotate


References

  1. ↑ Xiao B, Shi G, Chen X, Yan H, Ji X. Crystal structure of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase, a potential target for the development of novel antimicrobial agents. Structure. 1999 May;7(5):489-96. PMID:10378268
  2. ↑ Yogavel M, Nettleship JE, Sharma A, Harlos K, Jamwal A, Chaturvedi R, Sharma M, Jain V, Chhibber-Goel J, Sharma A. Structure of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase-dihydropteroate synthase from Plasmodium vivax sheds light on drug resistance. J Biol Chem. 2018 Aug 13. pii: RA118.004558. doi: 10.1074/jbc.RA118.004558. PMID:30104413 doi:http://dx.doi.org/10.1074/jbc.RA118.004558

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