Chemical composition and the potential for proteomic transformation in cancer, hypoxia, and hyperosmotic stress

Abstract

The changes of protein expression that are monitored in proteomic experiments are a type of biological transformation that also involves changes in chemical composition. Accompanying the myriad molecular-level interactions that underlie any proteomic transformation, there is an overall thermodynamic potential that is sensitive to microenvironmental conditions, including local oxidation and hydration potential. Here, up- and down-expressed proteins identified in 71 comparative proteomics studies were analyzed using the average oxidation state of carbon (ZC) and water demand per residue (), calculated using elemental abundances and stoichiometric reactions to form proteins from basis species. Experimental lowering of oxygen availability (hypoxia) or water activity (hyperosmotic stress) generally results in decreased ZC or of up-expressed compared to down-expressed proteins. This correspondence of chemical composition with experimental conditions provides evidence for attraction of the proteomes to a low-energy state. An opposite compositional change, toward higher average oxidation or hydration state, is found for proteomic transformations in colorectal and pancreatic cancer, and in two experiments for adipose-derived stem cells. Calculations of chemical affinity were used to estimate the thermodynamic potentials for proteomic transformations as a function of fugacity of O2 and activity of H2O, which serve as scales of oxidation and hydration potential. Diagrams summarizing the relative potential for formation of up- and down-expressed proteins have predicted equipotential lines that cluster around particular values of oxygen fugacity and water activity for similar datasets. The changes in chemical composition of proteomes are likely linked with reactions among other cellular molecules. A redox balance calculation indicates that an increase in the lipid to protein ratio in cancer cells by 20% over hypoxic cells would generate a large enough electron sink for oxidation of the cancer proteomes. The datasets and computer code used here are made available in a new R package, canprot.

Distinct trends in chemical composition of proteins from metagenomes in redox and salinity gradients

“…Similarly, cancer tissues are characterized by up-regulation of unicellular genes 69 as well as proteins with higher n H 2 O compared to normal tissue 17 . More work is needed to confirm whether hydration state decreases through the evolution of multicellularity, as suggested by these preliminary observations.…”

“…To probe into the physiological basis for the patterns found in metagenomes and metatranscriptomes, we considered the changes in transcripts and protein expression levels when cells are exposed to hyperosmotic conditions in the laboratory. differentially expressed proteins reported in 13 studies on non-halophilic bacterial and eukaryotic cells were summarized in a previous publication 17 . We augmented that compilation with data from an additional seven studies on bacteria and archaea [57][58][59][60][61][62][63] , including four halophiles ( Table 2).…”

“…The charge for each ionizable group was precalculated from pH 0 to 14 at intervals of 0.01, and the isoelectric point was computed as the pH where the sum of charges of all groups in the protein is closest to zero. These calculations were implemented as new functions in version 0.1.5 of the canprot package 17 for R 73 (see Data Availability). Comparisons for a few proteins show that the calculated values of GRAVY and pI are equal to those obtained with the ProtParam tool 78 .…”

“…Z C is computed from the chemical formulas of organic molecules, and takes values between the extremes of -4 (CH 4 ) and +4 (CO 2 ), although the range for particular classes of biomolecules is much smaller 15 . n H 2 O is derived from the number of water molecules in theoretical formation reactions of proteins from basis species 16,17 . Through analysis of representative metagenomic and metatranscriptomic datasets, we show that Z C and n H 2 O are most closely aligned with environmental redox and salinity gradients, respectively.…”

Water as a reactant in the differential expression of proteins in cancer

“…My previous analysis of proteomic data provided prelim- inary evidence for a higher hydration state of proteomes in colorectal and pancreatic cancer (19). That compilation of differential expression data is expanded here to include breast, liver, lung and prostate cancer.…”