Summary Archaeal and eukaryotic translation elongation factor 2 contain a unique posttranslationally modified histidine residue called “diphthamide”, the target of diphtheria toxin. The biosynthesis of diphthamide were proposed to involve three steps, with the first step being the formation of a C-C bond between the histidine residue and the 3-amino-3-carboxypropyl group of S-adenosylmethionine (SAM). However, details of the biosynthesis have remained unknown. Here we present structural and biochemical evidence showing that the first step of diphthamide biosynthesis in the archaeon Pyrococcus horikoshii uses a novel iron-sulfur cluster enzyme, Dph2. Dph2 is a homodimer and each monomer contains a [4Fe-4S] cluster. Biochemical data suggest that unlike the enzymes in the radical SAM superfamily, Dph2 does not form the canonical 5′-deoxyadenosyl radical. Instead, it breaks the Cγ,Met-S bond of SAM and generates a 3-amino-3-carboxylpropyl radical. This work suggests that Pyrococcus horikoshii Dph2 represents a novel SAM-dependent [4Fe-4S]-containing enzyme that catalyzes unprecedented chemistry.

OBJECTIVE: To synthesize the literature on associations between social determinants of health and pregnancy-related mortality and morbidity in the United States and to highlight opportunities for intervention and future research. DATA SOURCES: We performed a systematic search using Ovid MEDLINE, CINAHL, Popline, Scopus, and ClinicalTrials.gov (1990–2018) using MeSH terms related to maternal mortality, morbidity, and social determinants of health, and limited to the United States. METHODS OF STUDY SELECTION: Selection criteria included studies examining associations between social determinants and adverse maternal outcomes including pregnancy-related death, severe maternal morbidity, and emergency hospitalizations or readmissions. Using Covidence, three authors screened abstracts and two screened full articles for inclusion. TABULATION, INTEGRATION, AND RESULTS: Two authors extracted data from each article and the data were analyzed using a descriptive approach. A total of 83 studies met inclusion criteria and were analyzed. Seventy-eight of 83 studies examined socioeconomic position or individual factors as predictors, demonstrating evidence of associations between minority race and ethnicity (58/67 studies with positive findings), public or no insurance coverage (21/30), and lower education levels (8/12), and increased incidence of maternal death and severe maternal morbidity. Only 2 of 83 studies investigated associations between these outcomes and socioeconomic, political, and cultural context (eg, public policy), and 20 of 83 studies investigated material and physical circumstances (eg, neighborhood environment, segregation), limiting the diversity of social determinants of health studied as well as evaluation of such evidence. CONCLUSION: Empirical studies provide evidence for the role of race and ethnicity, insurance, and education in pregnancy-related mortality and severe maternal morbidity risk, although many other important social determinants, including mechanisms of effect, remain to be studied in greater depth. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42018102415.