Puromycin, a selective inhibitor of PSA acts as a substrate for other M1 family aminopeptidases: Biochemical and structural basis

Reddi, Ravikumar; Ganji, Roopa Jones; Marapaka, Anil Kumar; Bala, Sandeep Chowdary; Yerra, Naga Veera; Haque, Neshatul; Addlagatta, A.

doi:10.1016/j.ijbiomac.2020.10.035

“…Addlagatta and colleagues have suggested a binding mode for the PSA specific inhibitor puromycin based on the structure of puromycin bound to an inactive mutant of ePepN and docking to a closed form PSA homology model [ 112 ]. The nucleoside portion of the inhibitor interacts near the active site zinc ion and coordinating residues, while the remainder of the molecule extends toward helix 31 of domain IV.…”

Section: Discussionmentioning

confidence: 99%

“…In this position, a number of PSA side chains are placed to interact with the ligand, primarily from helix 11 of domain II and helix 31 of domain IV ( Fig 12B ). Puromycin soaked into crystals of active ePepN showed hydrolysis products in the active site [ 112 ]. Superimposing that structure on the closed model of PSA shows that O-methyl-L-tyrosine (OMT) fits well into the S1 subsite of the PSA closed model ( Fig 12C ).…”

Section: Discussionmentioning

confidence: 99%

“…(A) Docking of puromycin with the closed form PSA using ROSIE Ligand_docking [ 113 – 115 ]. Puromycin shown with yellow carbon atoms is from superposition of an inactive ePepN-puromycin complex reported by Addlagatta and colleagues [ 112 ] on the closed PSA model. That puromycin pose was used as the starting point for docking with the closed PSA model.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Structure of puromycin-sensitive aminopeptidase and polyglutamine binding

Madabushi

¹

,

Chow

²

,

Song

³

et al. 2023

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Puromycin-sensitive aminopeptidase (E.C. 3.4.11.14, UniProt P55786), a zinc metallopeptidase belonging to the M1 family, degrades a number of bioactive peptides as well as peptides released from the proteasome, including polyglutamine. We report the crystal structure of PSA at 2.3 Ǻ. Overall, the enzyme adopts a V-shaped architecture with four domains characteristic of the M1 family aminopeptidases, but it is in a less compact conformation compared to most M1 enzymes of known structure. A microtubule binding sequence is present in a C-terminal HEAT repeat domain of the enzyme in a position where it might serve to mediate interaction with tubulin. In the catalytic metallopeptidase domain, an elongated active site groove lined with aromatic and hydrophobic residues and a large S1 subsite may play a role in broad substrate recognition. The structure with bound polyglutamine shows a possible interacting mode of this peptide, which is supported by mutation.

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“…12B). Puromycin soaked into crystals of active ePepN showed hydrolysis products in the active site [112].…”

Section: Hydrolysis Of Polyglutamine Peptidesmentioning

confidence: 99%

“…Addlagatta and colleagues have suggested a binding mode for the PSA specific inhibitor puromycin based on the structure of puromycin bound to an inactive mutant of ePepN and docking to a closed form PSA homology model[112]. The nucleoside portion of the inhibitor interacts near the active site zinc ion and coordinating residues, while the remainder of the molecule extends toward helix 31 of domain IV.…”

mentioning

confidence: 99%

Structure of puromycin-sensitive aminopeptidase and polyglutamine binding

Madabushi

¹

,

Chow

²

,

Song

³

et al. 2023

Preprint

0

View full text Add to dashboard Cite

Puromycin-sensitive aminopeptidase (E.C. 3.4.11.14, UniProt P55786), a zinc metallopeptidase belonging to the M1 family, degrades a number of bioactive peptides as well as peptides released from the proteasome, including polyglutamine. We report the crystal structure of PSA at 2.3 Ǻ. Overall, the enzyme adopts a V-shaped architecture with four domains characteristic of the M1 family aminopeptidases, but it is in a less compact conformation compared to most M1 enzymes of known structure. A microtubule binding sequence is present in a C-terminal HEAT repeat domain of the enzyme in a position where it might serve to mediate interaction with tubulin. In the catalytic metallopeptidase domain, an elongated active site groove lined with aromatic and hydrophobic residues and a large S1 subsite may play a role in broad substrate recognition. The structure with bound polyglutamine shows a possible interacting mode of this peptide, which is supported by mutation.

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Bestatin attenuates breast cancer stemness by targeting puromycin-sensitive aminopeptidase

Ma,

Yang,

Pan

et al. 2024

Discov Onc

0

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Breast cancer is a prevalent malignant tumor among women with an increasing incidence rate annually. Breast cancer stem cells (BCSCs) are integral in impeding tumor advancement and addressing drug resistance. Bestatin serves as an adjuvant chemotherapy, triggering apoptosis in cancer cells. In this study, the effects of bestatin on sorted BCSCs from breast cancer cell lines have been studied. Our results indicated that bestatin inhibits the migration and proliferation of breast cancer cells by reducing the stemness of BCSCs both in vitro and in vivo. Puromycin-sensitive aminopeptidase is implicated in the process through the regulation of cell cycle, resulting in heightened cell apoptosis and diminished cell proliferation of BCSCs. Our study suggest that targeting cancer stem cell may offer a promising approach in breast cancer treatment, presenting noval therapeutic strategies for patients with breast cancer.

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Puromycin, a selective inhibitor of PSA acts as a substrate for other M1 family aminopeptidases: Biochemical and structural basis

Cited by 5 publications

References 29 publications

Structure of puromycin-sensitive aminopeptidase and polyglutamine binding

Structure of puromycin-sensitive aminopeptidase and polyglutamine binding

Structure of puromycin-sensitive aminopeptidase and polyglutamine binding

Bestatin attenuates breast cancer stemness by targeting puromycin-sensitive aminopeptidase

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