View source for 7wtc


==Cryo-EM structure of human pyruvate carboxylase with acetyl-CoA in the ground state==
<StructureSection load='7wtc' size='340' side='right'caption='[[7wtc]], [[Resolution|resolution]] 4.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7wtc]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WTC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WTC FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACO:ACETYL+COENZYME+*A'>ACO</scene>, <scene name='pdbligand=BTI:5-(HEXAHYDRO-2-OXO-1H-THIENO[3,4-D]IMIDAZOL-6-YL)PENTANAL'>BTI</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7wtc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wtc OCA], [https://pdbe.org/7wtc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wtc RCSB], [https://www.ebi.ac.uk/pdbsum/7wtc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wtc ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/PYC_HUMAN PYC_HUMAN] Defects in PC are the cause of pyruvate carboxylase deficiency (PC deficiency) [MIM:[https://omim.org/entry/266150 266150]. PC deficiency leads to lactic acidosis, mental retardation and death. It occurs in three forms: mild or type A, severe neonatal or type B, and a very mild lacticacidemia.
== Function ==
[https://www.uniprot.org/uniprot/PYC_HUMAN PYC_HUMAN] Pyruvate carboxylase catalyzes a 2-step reaction, involving the ATP-dependent carboxylation of the covalently attached biotin in the first step and the transfer of the carboxyl group to pyruvate in the second. Catalyzes in a tissue specific manner, the initial reactions of glucose (liver, kidney) and lipid (adipose tissue, liver, brain) synthesis from pyruvate.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Pyruvate carboxylase (PC) catalyzes the two-step carboxylation of pyruvate to produce oxaloacetate, playing a key role in the maintenance of metabolic homeostasis in cells. Given its involvement in multiple diseases, PC has been regarded as a potential therapeutic target for obesity, diabetes, and cancer. Albeit acetyl-CoA has been recognized as the allosteric regulator of PC for over 60 years, the underlying mechanism of how acetyl-CoA induces PC activation remains enigmatic. Herein, by using time-resolved cryo-electron microscopy, we have captured the snapshots of PC transitional states during its catalytic cycle. These structures and the biochemical studies reveal that acetyl-CoA stabilizes PC in a catalytically competent conformation, which triggers a cascade of events, including ATP hydrolysis and the long-distance communication between the two reactive centers. These findings provide an integrated picture for PC catalysis and unveil the unique allosteric mechanism of acetyl-CoA in an essential biochemical reaction in all kingdoms of life.

Mechanistic insight into allosteric activation of human pyruvate carboxylase by acetyl-CoA.,Chai P, Lan P, Li S, Yao D, Chang C, Cao M, Shen Y, Ge S, Wu J, Lei M, Fan X Mol Cell. 2022 Nov 3;82(21):4116-4130.e6. doi: 10.1016/j.molcel.2022.09.033. Epub, 2022 Oct 24. PMID:36283412<ref>PMID:36283412</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7wtc" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chai P]]
[[Category: Lan P]]
[[Category: Lei M]]
[[Category: Wu J]]