Immunosuppressive effect of a non-proteinogenic amino acid from Streptomyces through inhibiting allogeneic T cell proliferation.

The immunosuppressive activity of myriocin (ISP-1), a lead compound of fingolimod (FTY720), is derived from its 2-amino-1,3-propandiol structure. A non-proteinogenic amino acid, (2S,6R)-diamino-(5R,7)-dihydroxy-heptanoic acid (DADH), that contains this structure, was recently identified as a biosynthetic intermediate of a dipeptide secondary metabolite, vazabitide A, in Streptmyces sp. SANK 60404; however its effect on adaptive immunity has not yet been examined. In this study, we examined whether DADH suppresses mixed lymphocyte reaction using mouse bone marrow-derived dendritic cells (BMDCs) and allogeneic splenic T cells. Although T cell proliferation induced by cross-linking CD3 and CD28 were not suppressed by DADH unlike ISP-1, the pre-incubation of BMDCs with DADH but not ISP-1 significantly decreased allogeneic CD8+ T cell expansion. Based on these results, we concluded that DADH suppresses DC-mediated T cell activation by targeting DCs.

Structural determinants for substrate specificity of flavoenzymes oxidizing d-amino acids.

The oxidation of d-amino acids is relevant to neurodegenerative diseases, detoxification, and nutrition in microorganisms and mammals. It is also important for the resolution of racemic amino acid mixtures and the preparation of chiral building blocks for the pharmaceutical and food industry. Considerable biochemical and structural knowledge has been accrued in recent years on the enzymes that carry out the oxidation of the Cα-N bond of d-amino acids. These enzymes contain FAD as a required coenzyme, share similar overall three-dimensional folds and highly conserved active sites, but differ in their specificity for substrates with neutral, anionic, or cationic side-chains. Here, we summarize the current biochemical and structural knowledge regarding substrate specificity on d-amino acid oxidase, d-aspartate oxidase, and d-arginine dehydrogenase for which a wealth of biochemical and structural studies is available.

[Hyponatremias: From pathophysiology to treatments. Review for clinicians]. / Hyponatrémies : de la physiopathologie aux traitements. Revue de la littérature pour le clinicien.

Hyponatremia could be defined as a public health topic: too many patients are concerned in both hospitalized and general populations; hyponatremia induces lots of clinical outcomes and a great economic burden. Its pathophysiology involves thirst regulation (hypotonic water intakes) and losses regulation (through the kidney under vasopressin control). Diagnostic approach should insure that hyponatremia reflects hypo-osmolality and hypotonicity: first, a false hyponatremia should be ruled out, then a non-hypotonic one. Next step is clinic: extracellular status should be evaluated. When increased, any edematous status should be evoked: heart failure, liver cirrhosis or nephrotic syndrome. When decreased, any cause of extracellular dehydration should be evoked: natriuresis could help distinguishing between renal (adrenal insufficiency, diuretics use or salt-losing nephropathy) or extrarenal (digestive mostly) etiologies. When clinically normal, a secretion of inappropriate antidiuretic hormone (SIADH) should be evoked, once hypothyroidism or hypoadrenocorticism have been ruled out. Therapy depends on the severity of the clinical impact. From extracellular rehydration, through fluid restriction, the paraneoplastic and heart failure-induced SIADH benefit from a new class of drug, available among the therapeutic strategies: aquaretics act through antidiuretic hormone receptor antagonism (vaptans). Their long-term benefits still have to be proven but it is a significant step forward in the treatment of hyponatremias.