High-resolution structural-omics of human liver enzymes

Cell Rep. 2023 Jun 27;42(6):112609. doi: 10.1016/j.celrep.2023.112609. Epub 2023 Jun 7.


We applied raw human liver microsome lysate to a holey carbon grid and used cryo-electron microscopy (cryo-EM) to define its composition. From this sample we identified and simultaneously determined high-resolution structural information for ten unique human liver enzymes involved in diverse cellular processes. Notably, we determined the structure of the endoplasmic bifunctional protein H6PD, where the N- and C-terminal domains independently possess glucose-6-phosphate dehydrogenase and 6-phosphogluconolactonase enzymatic activity, respectively. We also obtained the structure of heterodimeric human GANAB, an ER glycoprotein quality-control machinery that contains a catalytic α subunit and a noncatalytic β subunit. In addition, we observed a decameric peroxidase, PRDX4, which directly contacts a disulfide isomerase-related protein, ERp46. Structural data suggest that several glycosylations, bound endogenous compounds, and ions associate with these human liver enzymes. These results highlight the importance of cryo-EM in facilitating the elucidation of human organ proteomics at the atomic level.

Keywords: CP: Metabolism; CP: Molecular biology; aldehyde oxidase 1; carboxylesterase 1; glucosidase II; glutamate dehydrogenase 1; glycogen phosphorylase; hexose-6-phosphate dehydrogenase; microsomal triglyceride transfer protein complex; peroxiredoxin 4 – endoplasmic reticulum protein 46 complex; retinaldehyde dehydrogenase 1; structural-omics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Catalytic Domain
  • Cryoelectron Microscopy
  • Endoplasmic Reticulum* / metabolism
  • Humans
  • Liver / metabolism
  • Protein Disulfide-Isomerases* / metabolism


  • Protein Disulfide-Isomerases