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Small molecule gases such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) have long been recognized as endogenous signaling molecules with diverse physiological roles. Often described as “gasotransmitters”, these molecules complement other small molecule bioregulators (SMBs) that exert biological function across all kingdoms of life. One underappreciated distinction, however, is that many of these molecules – irrespective of whether or not they are gases in their native states outside of biology – exhibit similar molecular signaling potential mediated by protonation-dependent chemical speciation. In this review, we propose the new cross-cutting classification of protic small molecule bioregulators (PSMBs) to describe molecules in which biological function and reactivity are modulated by protonation state. Examples of PSMBs include the canonical gasotransmitter H2S, emerging gasotransmitters (H2Se, HCN), small molecule crosstalk species (e.g., SNO–, SSNO–, SO42–, ONOO–, NO2–, SCN–, OCl–), and other species where protonation state modulation is accessible at physiological pH. Importantly, these species exist in equilibrium between their neutral and anionic forms, with speciation governed by local pH and molecular environment, directly impacting their membrane nucleophilicity, permeability, redox activity, and interaction with metal centers. We describe the evolutionary origins, biosynthesis, and crosstalk of PSMBs, including roles in redox signaling, post-translational modification, and mitochondrial regulation. Reframing these important molecules in a class defined by their protic ability rather than gaseous state does not diminish prior gasotransmitter designations, but rather serves to recognize commonalities in chemical characteristics that drive the unique biological chemistry and regulation. 

Nucleotide sequence reagents underpin molecular techniques that have been applied across hundreds of thousands of publications. We have previously reported wrongly identified nucleotide sequence reagents in human research publications and described a semi-automated screening tool Seek & Blastn to fact-check their claimed status. We applied Seek & Blastn to screen >11,700 publications across five literature corpora, including all original publications in Gene from 2007 to 2018 and all original open-access publications in Oncology Reports from 2014 to 2018. After manually checking Seek & Blastn outputs for >3,400 human research articles, we identified 712 articles across 78 journals that described at least one wrongly identified nucleotide sequence. Verifying the claimed identities of >13,700 sequences highlighted 1,535 wrongly identified sequences, most of which were claimed targeting reagents for the analysis of 365 human protein-coding genes and 120 non-coding RNAs. The 712 problematic articles have received >17,000 citations, including citations by human clinical trials. Given our estimate that approximately one-quarter of problematic articles may misinform the future development of human therapies, urgent measures are required to address unreliable gene research articles. 

Fluorinated 5-hydroxytryptophans (F n -5HOWs) were synthesized in gram scale quantities and incorporated into a β-hairpin peptide and the protein azurin. The redox-active F n -5HOWs exhibit unique radical spectroscopic signatures that expand the function of 5HOW as probes for biological electron transfer.