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TitleMechanistic insight into allosteric activation of human pyruvate carboxylase by acetyl-CoA.
Journal, issue, pagesMol Cell, Vol. 82, Issue 21, Page 4116-44130.e6, Year 2022
Publish dateNov 3, 2022
AuthorsPeiwei Chai / Pengfei Lan / Shaobai Li / Deqiang Yao / Chenchen Chang / Mi Cao / Yafeng Shen / Shengfang Ge / Jian Wu / Ming Lei / Xianqun Fan /
PubMed AbstractPyruvate 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 ...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.
External linksMol Cell / PubMed:36283412
MethodsEM (single particle)
Resolution3.3 - 4.0 Å
Structure data

32773

7wta

EMDB-32773, PDB-7wta:
Cryo-EM structure of human pyruvate carboxylase in apo state
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-32774: PC-(acetyl-CoA) (12.5uM)
Method: EM (single particle) / Resolution: 3.9 Å

32775

7wtb

EMDB-32775, PDB-7wtb:
Cryo-EM structure of human pyruvate carboxylase with acetyl-CoA
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-32776: PC-(acetyl-CoA)(50 uM)
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-32777: PC-(acetyl-CoA)(100 uM)
Method: EM (single particle) / Resolution: 3.6 Å

32778

7wtc

EMDB-32778, PDB-7wtc:
Cryo-EM structure of human pyruvate carboxylase with acetyl-CoA in the ground state
Method: EM (single particle) / Resolution: 4.0 Å

32779

7wtd

EMDB-32779, PDB-7wtd:
Cryo-EM structure of human pyruvate carboxylase with acetyl-CoA in the intermediate state 1
Method: EM (single particle) / Resolution: 3.9 Å

32780

7wte

EMDB-32780, PDB-7wte:
Cryo-EM structure of human pyruvate carboxylase with acetyl-CoA in the intermediate state 2
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-32781: Cryo-EM structure of human pyruvate carboxylase with acetyl-CoA in the intermediate state 3
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-32782: Cryo-EM structure of human pyruvate carboxylase with acetyl-CoA in the intermediate state 4
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-32783: Cryo-EM structure of human pyruvate carboxylase with acetyl-CoA in the intermediate state 5
Method: EM (single particle) / Resolution: 3.8 Å

Chemicals

ChemComp-BTI:
5-(HEXAHYDRO-2-OXO-1H-THIENO[3,4-D]IMIDAZOL-6-YL)PENTANAL

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

ChemComp-ACO:
ACETYL COENZYME *A

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-COA:
COENZYME A

Source
  • homo sapiens (human)
  • human (human)
KeywordsONCOPROTEIN / pyruvate carboxylase

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