According to Warburg effects, cancer cells are known to produce lactate as an end product
instead of pyruvate and accumulation of lactate is linked to metabolic reprogramming.
Hiowever, substantial exist in terms of the non-metabolic role of lactate including modification
of histones during epigenetic regulation, in particular.
This study employs in silico molecular docking and molecular dynamics study to determine
the potential mechanisms of lactylation on histone proteins that achieve epigenetic changes in
cancer and non-cancer cells. Here, we tested three potential substrate sources for lactylation,
namely lactate (CHEBI ID:24996), lactyl-CoA (CHEBI ID:15529) and (R)-Slactoylglutathione (PubChem ID-440018). A histone acetyltransferase p300 (HAT p300)
enzyme (PDB ID: 6GYR) was considered as a potential candidate for the lactylation process.
Among the studied substrates for the lactylation process, molecular docking reveals a highly
efficient binding affinity (docking energy -8.6 Kcal/Mol) of lacyl-CoA with p300 enzyme. On
the other hand, lactate and (R)-S-Lactoylglutathione did not shown any significant and specific
binding to HAT p300 enzyme. Furthermore, molecular dynamics simulation study suggestsa
stable binding of lactyl-CoA at the substrate-binding site of p300 with amino acid residues
ASP-1399, HIS1402, ARG-1410, THR1411, TYR1414, TRP1436, ASP1454 and LYS1456.
In conclusion, our data support that lactyl-CoA is a potential substrate for lactylation carried
out by the HAT p300 enzyme. However, lactyl-CoA is not detected at the physiological level
in cancer and non-cancer supporting cells such as macrophage. Based on our data and existing
views on lactylation, the authors propose an involvement of pro-tumor bacteria in this that
converts lactate to lactyl-CoA and lactyl-CoA is shuttled to the macrophage within the tumor
microenvironment. Due to lactyl-CoA entry into macrophages (anti-tumorigenic)s, lactylation
process allow the transcriptional changes and achieve the M1 to M2 macrophage polarization
(pro-tumor) and in turn, promotes the tumor growth and survival.
InstitutionDr. D.Y. Patil Biotechnology & Bioinformatics Institute, Pune
ORCID For Submitting Author0000-0002-8774-3020
Declaration of Conflict of InterestThe authors none conflict of interest.