Naturally-occurring spinosyn A and its derivatives function as argininosuccinate synthase activator and tumor inhibitor

Nat Commun. 2021 Apr 15;12(1):2263. doi: 10.1038/s41467-021-22235-8.

Abstract

Argininosuccinate synthase (ASS1) is a ubiquitous enzyme in mammals that catalyzes the formation of argininosuccinate from citrulline and aspartate. ASS1 genetic deficiency in patients leads to an autosomal recessive urea cycle disorder citrullinemia, while its somatic silence or down-regulation is very common in various human cancers. Here, we show that ASS1 functions as a tumor suppressor in breast cancer, and the pesticide spinosyn A (SPA) and its derivative LM-2I suppress breast tumor cell proliferation and growth by binding to and activating ASS1. The C13-C14 double bond in SPA and LM-2I while the Cys97 (C97) site in ASS1 are critical for the interaction between ASS1 and SPA or LM-2I. SPA and LM-2I treatment results in significant enhancement of ASS1 enzymatic activity in breast cancer cells, particularly in those cancer cells with low ASS1 expression, leading to reduced pyrimidine synthesis and consequently the inhibition of cancer cell proliferation. Thus, our results establish spinosyn A and its derivative LM-2I as potent ASS1 enzymatic activator and tumor inhibitor, which provides a therapeutic avenue for tumors with low ASS1 expression and for those non-tumor diseases caused by down-regulation of ASS1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Argininosuccinate Synthase / genetics
  • Argininosuccinate Synthase / isolation & purification
  • Argininosuccinate Synthase / metabolism*
  • Aspartic Acid / metabolism
  • Breast / pathology
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Citrulline / metabolism
  • Citrullinemia / drug therapy*
  • Citrullinemia / genetics
  • Enzyme Activators / pharmacology*
  • Enzyme Activators / therapeutic use
  • Female
  • Gene Knockdown Techniques
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Macrolides / pharmacology*
  • Macrolides / therapeutic use
  • Metabolomics
  • Mice
  • Middle Aged
  • Molecular Docking Simulation
  • Mutation
  • Protein Binding
  • Pyrimidines / biosynthesis
  • Recombinant Proteins / genetics
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Tumor Suppressor Proteins / agonists*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Enzyme Activators
  • Macrolides
  • Pyrimidines
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • spinosyn A
  • Citrulline
  • Aspartic Acid
  • Argininosuccinate Synthase
  • pyrimidine