Impairment of the mitochondrial one-carbon metabolism enzyme SHMT2 causes a novel brain and heart developmental syndrome

Inborn errors of metabolism cause a wide spectrum of neurodevelopmental and neurodegenerative conditions [15]. A pivotal enzyme located at the intersection of the amino acid and folic acid metabolic pathways is SHMT2, the mitochondrial form of serine hydroxymethyltransferase. SHMT2 performs the first step in a series of reactions that provide one-carbon units covalently bound to folate species in mitochondria: it transfers one-carbon units from serine to tetrahydrofolate (THF), generating glycine and 5,10-methylene-THF. Using whole exome sequencing (WES), we identified biallelic SHMT2 variants in five individuals from four different families. All identified variants were located in conserved residues, either absent or extremely rare in control databases (gnomAD, ExAC), and cosegregated based on a recessive mode of inheritance (pRec = 0.9918 for this gene). In family F1, a homozygous missense variant present in two affected siblings was located in a region without heterozygosity (~ 10 Mb, the only region > 1 Mb shared by both siblings) in which no other candidate variants were found, providing a strong genetic evidence of causality for these variants. The missense/in-frame deletion nature of these variants, and the absence of loss-of-function homozygous individuals in control databases, combined with the fact that complete loss of SHMT2 is embryonic lethal in the mouse, suggested that these variants may cause hypomorphic effects. Using 3D molecular dynamics models of the SHMT2 protein, we concluded that these candidate variants probably alter the SHMT2 oligomerization process, and/or disrupt the conformation of the active site, thus inducing deleterious effects on SHMT2 enzymatic function

Chemistry of Bridged Vitamin K Model Compounds

Color poster with text, graphs, diagrams, and charts.Warfarin (Coumadin) has been in extensive clinical use since 1954. Although widely prescribed, warfarin is associated with a high incidence of adverse drug events (ADEs). This study continues research begun in 2009 when two vitamin K analogues (UWEC-K1 and UWEC-K2) that can potentially act as a warfarin agonist, were discovered.University of Wisconsin--Eau Claire Office of Research and Sponsored Programs; WiSys Technology Foundation

Synthesis, Properties, and Reactions of Vitamin K Analogs

Color poster with text, diagrams, and graphs.The synthesis of new vitamin K analogs has been undertaken. We have recently reported that two of these compounds act as in vivo adjuvants that enhance anticogulant activity of Warfarin in rats. The prepartation and characterization of these compounds is being continued with the aim to synthesize new oral anticoagulant compounds.University of Wisconsin--Eau Claire Office of Research and Sponsored Programs; WISys Technology Fund; Marshfield Clinic Research Foundatio