All organisms produce specialized organic molecules, ranging from small volatile chemicals to large gene-encoded peptides, that have evolved to provide them with diverse cellular and ecological functions. As natural products, they are broadly applied in medicine, agriculture and nutrition. The rapid accumulation of genomic information has revealed that the metabolic capacity of virtually all organisms is vastly underappreciated. Pioneered mainly in bacteria and fungi, genome mining technologies are accelerating metabolite discovery. Recent efforts are now being expanded to all life forms, including protists, plants and animals, and new integrative omics technologies are enabling the increasingly effective mining of this molecular diversity.

Mining genomes to illuminate the specialized chemistry of life

Interleukin-4-induced-1 (IL4i1) is an amino acid oxidase secreted from immune cells. Recent observations have suggested that IL4i1 is pro-tumorigenic via unknown mechanisms. As IL4i1 has homologs in snake venoms (L-amino acid oxidases [LAAO]), we used comparative approaches to gain insight into the mechanistic basis of how conserved amino acid oxidases regulate cell fate and function. Using mammalian expressed recombinant proteins, we found that venom LAAO kills cells via hydrogen peroxide generation. By contrast, mammalian IL4i1 is non-cytotoxic and instead elicits a cell protective gene expression program inhibiting ferroptotic redox death by generating indole-3-pyruvate (I3P) from tryptophan. I3P suppresses ferroptosis by direct free radical scavenging and through the activation of an anti-oxidative gene expression program. Thus, the pro-tumor effects of IL4i1 are likely mediated by local anti-ferroptotic pathways via aromatic amino acid metabolism, arguing that an IL4i1 inhibitor may modulate tumor cell death pathways.

/pdf/anti-ferroptotic-mechanism-of-il4i1-mediated-amino-acid-5bq7wof6kf.pdf

Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism.

Fine-tuned by millions of years of evolution, snake venoms have frightened but also fascinated humanity and nowadays they constitute potential resources for drug development, therapeutics and antivenoms. The continuous progress of mass spectrometry techniques and latest advances in proteomics workflows enabled toxinologists to decipher venoms by modern omics technologies, so-called 'venomics'. A tremendous upsurge reporting on snake venom proteomes could be observed. Within this review we focus on the highly venomous and widely distributed subfamily of Viperinae (Serpentes: Viperidae). A detailed public literature database search was performed (2003-2020) and we extensively reviewed all compositional venom studies of the so-called Old-World Vipers. In total, 54 studies resulted in 89 venom proteomes. The Viperinae venoms are dominated by four major, four secondary, six minor and several rare toxin families and peptides, respectively. The multitude of different venomics approaches complicates the comparison of venom composition datasets and therefore we differentiated between non-quantitative and three groups of quantitative workflows. The resulting direct comparisons within these groups show remarkable differences on the intra- and interspecies level across genera with a focus on regional differences. In summary, the present compilation is the first comprehensive up-to-date database on Viperinae venom proteomes and differentiating between analytical methods and workflows.

/pdf/old-world-vipers-a-review-about-snake-venom-proteomics-of-571kcpgkpv.pdf

Old World Vipers—A Review about Snake Venom Proteomics of Viperinae and Their Variations

Advancements in capturing and mining mass spectrometry data are transforming natural products research

Venomic research, powered by techniques adapted from proteomics, transcriptomics, and genomics, seeks to unravel the diversity and complexity of venom through which knowledge can be applied in the treatment of envenoming, biodiscovery, and conservation. Snake venom proteomics is most extensively studied, but the methods varied widely, creating a massive amount of information which complicates data comparison and interpretation. Advancement in mass spectrometry technology, accompanied by growing databases and sophisticated bioinformatic tools, has overcome earlier limitations of protein identification. The progress, however, remains challenged by limited accessibility to samples, non-standardized quantitative methods, and biased interpretation of -omic data. Next-generation sequencing (NGS) technologies enable high-throughput venom-gland transcriptomics and genomics, complementing venom proteomics by providing deeper insights into the structural diversity, differential expression, regulation and functional interaction of the toxin genes. Venomic tissue sampling is, however, difficult due to strict regulations on wildlife use and transfer of biological materials in some countries. Limited resources for techniques and funding are among other pertinent issues that impede the progress of venomics, particularly in less developed regions and for neglected species. Genuine collaboration between international researchers, due recognition of regional experts by global organizations (e.g., WHO), and improved distribution of research support, should be embraced.

/pdf/snake-venomics-fundamentals-recent-updates-and-a-look-to-the-5qwjpwnp.pdf

Snake Venomics: Fundamentals, Recent Updates, and a Look to the Next Decade

Convergent evolution provides insights into the selective drivers underlying evolutionary change. Snake venoms, with a direct genetic basis and clearly defined functional phenotype, provide a model system for exploring the repeated evolution of adaptations. While snakes use venom primarily for predation, and venom composition often reflects diet specificity, three lineages of cobras have independently evolved the ability to spit venom at adversaries. Using gene, protein, and functional analyses, we show that the three spitting lineages possess venoms characterized by an up-regulation of phospholipase A2 (PLA2) toxins, which potentiate the action of preexisting venom cytotoxins to activate mammalian sensory neurons and cause enhanced pain. These repeated independent changes provide a fascinating example of convergent evolution across multiple phenotypic levels driven by selection for defense.

/pdf/convergent-evolution-of-pain-inducing-defensive-venom-1s762r6syc.pdf

Convergent evolution of pain-inducing defensive venom components in spitting cobras

Convergent evolution provides unparalleled insights into the selective drivers underlying evolutionary change. While snakes use venom primarily for predation, and venom composition often reflects diet specificity, three lineages of spitting cobras have independently evolved the ability to use venom as a defensive projectile. Using gene, protein and functional analyses, we show that the three spitting lineages possess venom characterized by an upregulation of PLA2 toxins, which potentiate the action of venom cytotoxins to activate mammalian sensory neurons and cause enhanced pain. These repeated independent changes provide a fascinating example of convergent evolution across multiple phenotypic levels driven by exaptations. Notably, the timing of their origins suggests that defensive venom spitting may have evolved in response to the emergence of bipedal hominids in Africa and Asia. One Sentence Summary Venom spitting by snakes coincides with the emergence of hominins and is underpinned by convergent increases in pain-enhancing toxins

/pdf/convergent-evolution-of-pain-inducing-defensive-venom-v3grn8k4g8.pdf

Convergent Evolution of Pain-Inducing Defensive Venom Components in Spitting Cobras

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Convergent evolution of pain-inducing defensive venom components in spitting cobras

Convergent Evolution of Pain-Inducing Defensive Venom Components in Spitting Cobras