Late-Stage Chemoenzymatic Installation of Hydroxy-Bearing Allyl Moiety on the Indole Ring of Tryptophan-Containing Peptides

The late-stage functionalization of indole- and tryptophan-containing compounds with reactive moieties facilitates downstream diversification and leads to changes in their biological properties. Here, the synthesis of two hydroxy-bearing allyl pyrophosphates is described. A chemoenzymatic method is demonstrated which uses a promiscuous indole prenyltransferase enzyme to install a dual reactive hydroxy-bearing allyl moiety directly on the indole ring of tryptophan-containing peptides. This is the first report of late-stage indole modifications with this reactive group

Physiological Roles of Mammalian Transmembrane Adenylyl Cyclase Isoforms

Adenylyl cyclases (ACs) catalyze the conversion of ATP to the ubiquitous second messenger cAMP. Mammals possess nine isoforms of transmembrane ACs, dubbed AC1-9, that serve as major effector enzymes of G protein-coupled receptors. The transmembrane ACs display varying expression patterns across tissues, giving potential for them having a wide array of physiologic roles. Cells express multiple AC isoforms, implying that ACs have redundant functions. Furthermore, all transmembrane ACs are activated by Gαs so it was long assumed that all ACs are activated by Gαs-coupled GPCRs. AC isoforms partition to different microdomains of the plasma membrane and form prearranged signaling complexes with specific GPCRs that contribute to cAMP signaling compartments. This compartmentation allows for a diversity of cellular and physiological responses by enabling unique signaling events to be triggered by different pools of cAMP. Isoform specific pharmacological activators or inhibitors are lacking for most ACs, making knockdown and overexpression the primary tools for examining the physiological roles of a given isoform. Much progress has been made in understanding the physiological effects mediated through individual transmembrane ACs. GPCR-AC-cAMP signaling pathways play significant roles in regulating functions of every cell and tissue, so understanding each AC isoform\u27s role holds potential for uncovering new approaches for treating a vast array of pathophysiological conditions

Perceptions of climate change, multiple stressors and livelihoods on marginal African coasts

Studies of multiple stressors in Africa often focus on vulnerable inland communities. Rising concentrations of the world’s poor live in coastal rural–urban areas with direct dependencies on marine as well as terrestrial ecosystem goods and services. Using participatory methods we elicited perceptions of stressors and their sources, impacts and consequences held by coastal communities in eastern Africa (Mtwara in Tanzania and Maputo in Mozambique). Respondent-informed timelines suggest wars, economic policies and natural increase have led to natural resource-dependent populations in marginal, previously little-inhabited lowland coastal areas. Respondents (n = 91) in interviews and focus groups rank climate stressors (temperature rise/erratic rain) highest amongst human/natural stressors having negative impacts on livelihoods and wellbeing (e.g., cross-scale cost of living increases including food and fuel prices). Sources of stress and impacts were mixed in time and space, complicating objective identification of causal chains. Some appeared to be specific to coastal areas. Respondents reported farms failing and rising dependence on stressed marine resources, food and fuel prices and related dependence on traders and credit shrunk by negative global market trends. Development in the guise of tourism and conservation projects limited access to land–sea livelihoods and resources in rural–urban areas (coastal squeeze). Mental modelling clarified resource user perceptions of complex linkages from local to international levels. We underline risks of the poor in marginal coastal areas facing double or multiple exposures to multiple stressors, with climate variability suggesting the risks of climate change