The retinoid X receptor (RXR) participates in a wide array of hormonal signaling pathways, either as a homodimer or as a heterodimer, with other members of the steroid and thyroid hormone receptor superfamily. In this report the ligand-dependent transactivation function of RXR has been characterized, and the ability of RXR to interact with components of the basal transcription machinery has been examined. In vivo and in vitro experiments indicate the RXR ligand-binding domain makes a direct, specific, and liganddependent contact with a highly conserved region of the TATA-binding protein. The ability of mutations that reduce ligand-dependent transcription by RXR to disrupt the RXR-TATA-binding protein interaction in vivo and in vitro suggests that RXR makes direct contact with the basal transcription machinery to achieve activation.Members of the steroid and thyroid hormone receptor (TR) superfamily regulate expression of complex gene networks involved in vertebrate development, differentiation, and homeostasis. A defining characteristic of these receptors lies in part in their ability to function as ligand-activated transcription factors. Retinoid X receptors (RXRs) occupy a central position in the function and activity of receptors for thyroid hormones and vitamins. By forming heterodimers with retinoic acid receptors (RARs), TRs, vitamin D receptors (VDRs), peroxisome proliferator activated receptors (PPARs), and several orphan receptors, RXRs participate in a diverse array of signaling pathways (1). The ability of RXR homodimers to respond to 9-cis-retinoic acid identifies still another signaling pathway influenced by this nuclear receptor. The critical role for RXRs in the function of nuclear receptors is further highlighted by the structural and functional conservation between vertebrate RXRs and the Drosophila nuclear receptor ultraspiricle (2).The mechanism by which RXR (and other nuclear receptors) activates transcription is poorly understood. Numerous studies have defined two independent transactivation functions (tau domains, T) in most members of the steroid and TR superfamily. These activation functions include a constitutive activation function (X1 or AF-1) present in the amino-terminal region and a ligand-dependent activation function (rc or AF-2) present in the carboxyl-terminal 200-250 amino acids. The carboxyl-terminal domain of nuclear receptors is complex, mediating ligand-dependent activation, receptor homo-and heterodimerization, and ligand binding. Binding of ligand is thought to induce a conformational change in receptors that leads to activation of transcription (3, 4).How activated receptors propagate their signals to the basal transcription machinery is not known. Direct interactions between the basal transcription factor TFIIB and several nuclear receptors have been reported (5-9). The nuclear receptor-TFIIB interaction does not appear to be influenced by ligand, and it has been suggested that interaction between TR and TFIIB may be associated with transcriptional repression (6...

PLP is well-regarded for its role as a coenzyme in a number of diverse enzymatic reactions. Transamination, deoxygenation, and aldol reactions mediated by PLP-dependent enzymes enliven and enrich deoxy sugar biosynthesis, endowing these compounds with unique structures and contributing to their roles as determinants of biological activity in many natural products. The importance of deoxy amino sugars in natural product biosynthesis has spurred several recent structural investigations of sugar aminotransferases. The structure of a PMP-dependent enzyme catalyzing the C-3 deoxygenation reaction in the biosynthesis of ascarylose was also determined. These studies, and the crystal structures they have provided, offer a wealth of new insights regarding the enzymology of PLP/PMP-dependent enzymes in deoxy sugar biosynthesis. In this review, we consider these recent achievements in the structural biology of deoxy sugar biosynthetic enzymes and the important implications they hold for understanding enzyme catalysis and natural product biosynthesis in general.

A combination of modified ultrafiltration, hemodialysis, and the administration of recombinant factor VIIa, fresh frozen plasma, and cryoprecipitate may reverse the anticoagulant effect of bivalirudin.

Peptidyl nucleoside antibiotics (PNAs) are a diverse class of natural products with promising biomedical activities. These compounds have tripartite structures composed of a core saccharide, a nucleobase, and one or more amino acids. In particular, amipurimycin and the miharamycins are novel 2-aminopurinyl PNAs with complex nine-carbon core saccharides and include the unusual amino acids (–)-cispentacin and N5-hydroxyarginine, respectively. Despite their interesting structures and properties, these PNAs have heretofore eluded biochemical scrutiny. Herein is reported the discovery and initial characterization of the miharamycin gene cluster in Streptomyces miharaensis (mhr) and the amipurimycin gene cluster (amc) in Streptomyces novoguineensis and Streptomyces sp. SN-C1. The gene clusters were identified using a comparative genomics approach, and heterologous expression of the amc cluster as well as gene interruption experiments in the mhr cluster support their role in the biosynthesis of amipurimycin and the miharamycins, respectively. The mhr and amc biosynthetic gene clusters characterized encode enzymes typical of polyketide biosynthesis instead of enzymes commonly associated with PNA biosynthesis, which along with labeled precursor feeding studies, implies that the core saccharides found in the miharamycins and amipurimycin are partially assembled as polyketides rather than derived solely from carbohydrates. Furthermore, in vitro analysis of Mhr20 and Amc18 established their roles as ATP-grasp ligases involved in the attachment of the pendant amino acids found in these PNAs, and Mhr24 was found to be an unusual hydroxylase involved in the biosynthesis of N5-hydroxyarginine. Finally, analysis of the amc cluster and feeding studies also led to the proposal of a biosynthetic pathway for (–)-cispentacin.

IRORAN is a growing problem, particularly in children and adolescents, secondary to the increase in the prevalence of obesity. Treatment of IRONAN should focus on reversal of the underlying hyperinsulinemia. Patients with IRORAN may benefit from a trial of metformin for improvement of lesions and underlying hyperinsulinemia.