Ornithine 500mg capsules

Human ornithine aminotransferase (hOAT) is a mitochondrial matrix pyridoxal-5'-phosphate enzyme (PLP) that catalyzes the reversible transfer of the δ-amino group of L-ornithine (L-Orn) to α-ketoglutarate (α-KG) yielding glutamate-5-semialdehyde (GSA) and glutamate. GSA is prone to cyclize to Δ1-pyrroline-5-carboxylate. Human OAT holds significant clinical and scientific interest because (i) its dysfunction causes gyrate atrophy (GA) of the choroid and retina, a rare autosomal recessive disease, and (ii) it is recognized as a potential target for chemotherapeutic drug development, being overexpressed in some types of cancer. Here, we review the kinetic and structural features of the enzyme, as well as the mechanistic aspects of hOAT inhibition. Moreover, we focus our attention on the characterization of the structural and functional properties of the artificial variants and of those associated with GA. Considering that great progress toward the characterization of the pathogenic variants has been reached in the last few years, we summarize here, by revisiting the data available on the hOAT and its variants as purified recombinant form, the current understanding of (i) the molecular defect(s) of studied disease-causing mutations and (ii) the residues (particularly, active site residues critical for dictating the reaction specificity) and/or regions of the enzyme crucial for its folding and/or catalytic properties.

Abstract licence: CC BY

A conductive matrix not only supports cell growth but also provides the potential to stimulate the cells. However, electrically conductive matrices often require synthetic polymers, nanomaterials, and a large number of ionic species. While enhancing electrical conductivity, often properties like transparency, mechanical stiffness, and biocompatibility are compromised, which can subvert suitability for neural tissue engineering. Further, the byproducts of matrix degradation can have unforeseen influences. Therefore, electrically active matrices are required that provide a suitable combination of electrical conductivity, mechanical properties, and biocompatibility in combination with bioprinting capability. Here, a novel biomaterial is described which is optically transparent, electrically conductive and highly biocompatible. We covalently incorporated zwitterionic functional groups in gelatin methacryloyl (GelMA) to obtain a composite matrix. The zwitterionic moieties were derived from Ornithine by synthesizing ornithine methacryloyl (OrnMA). Systematically, we demonstrated the suitability of GelMA-OrnMA hydrogels in providing stiffness matching the native neural tissues, supporting proliferation of human astrocytes in 3D culture, and electrical conductivity in the range required for electrically active cell types like astrocytes. Owing to their electrical conductivity, these matrices also influenced the growth of astrocytes, manifesting as changes in their organization and morphology. These findings suggest that GelMA-OrnMA has immense potential for developing engineered neural tissues.

Abstract licence: CC BY

Realgar, an arsenic-containing traditional Chinese medicine, is commonly used in clinical practice. However, prolonged, excessive, or uncontrolled administration of Chinese patent medicines containing realgar can occasionally induce adverse effects. Notably, realgar-induced central nervous system (CNS) toxicity has garnered significant attention. To elucidate the molecular mechanism underlying realgar-induced CNS toxicity, conditional intervention animal models (Zbtb7aGfABC1D KD/OtcTBG OE/chrysophanol intervention) are established and exposed to realgar, and a C8-D1A astrocyte cell line transfected with si-Zbtb7a is established and exposed to both iAs3+ and ornithine. Single-cell transcriptome sequencing, metabolomic analysis, as well as neurobehavioral, molecular biological, and histopathological experiments are performed. These results demonstrate that arsenic derived from realgar crosses the blood-brain barrier and accumulates in the frontal lobe. Within astrocytes, arsenic triggers ZBTB7A-mediated transcriptional repression of the glycolytic genes Aldoa, Ldha, and Pgam1, consequently reducing lactic acid levels. This cascade of events culminates in energy deficits within the frontal lobe, promoting apoptosis and oxidative damage. These pathological changes manifest behaviorally as decreased learning and memory capacity, diminished spontaneous exploration, and the development of anxiety-like behaviors. Furthermore, realgar inhibits hepatic ornithine transcarbamylase (OTC), disrupting the hepatic ornithine cycle. This disruption leads to ornithine accumulation, which in turn modulates the transcription factor ZBTB7A in astrocytes, indirectly exacerbating the neurotoxic effects of arsenic. In addition, chrysophanol antagonizes the toxic effects of realgar on the CNS and liver by protecting astrocyte glycolytic function and the hepatic ornithine cycle. This study provides new perspectives and targets for the prevention and treatment of realgar-induced neurological injuries, as well as new experimental bases and theoretical guidance for the use of rhubarb and realgar in traditional Chinese medicine.

Abstract licence: CC BY

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are remarkable natural products with interesting chemical structures and potent bioactivities. RiPP pathways are abundant in all domains of life and harbor a large biosynthetic potential in the form of post-translationally acting enzymes. A relatively small number of RiPP biosynthetic gene clusters encode peptide arginases, a recently discovered maturase family capable of hydrolyzing arginine residues of RiPP core peptides to ornithines. In this study, members of the peptide arginase family (FlmR and OhkR), which are associated with uncharacterized precursors from orphan RiPP families, are identified. In vivo and in vitro activity of FlmR and OhkR with the five associated precursor peptides (FlmA1-3 and OhkA1-2) is demonstrated and kinetic studies to biochemically characterize the enzymes are performed. Furthermore, in silico structural analysis with AlphaFold 3 is used to predict precursor-arginase complexes, providing insights into how peptide arginases could bind their precursor substrates. In the case of OhkA-OhkR complexes, this analysis also allows a hypothesis as to which of the arginine residues of the core peptide is modified first, which is confirmed experimentally. This detailed biochemical and structural enzyme characterization is a prerequisite for the application of peptide arginases in peptide-based drug discovery platforms.

Abstract licence: CC BY

Cationic amino acid transporter 1 (CAT1) transports cationic amino acids and plays pivotal roles in cancer proliferation, immune modulation, and nitric oxide metabolism. It also serves as the specific cellular receptor for certain murine leukemia viruses. Here, we report the cryo-electron microscopy (cryo-EM) structure of mammalian CAT1 in complex with its substrate ornithine and the receptor-binding domain (RBD) of Friend murine leukemia virus (FrMLV). CAT1 specifically recognizes the side-chain amino group of ornithine via residue S347 on transmembrane helix 8 (TM8), capturing the transporter in an inward-facing occluded conformation. Notably, the FrMLV RBD (frRBD) primarily engages the third extracellular loop (ECL3) of CAT1-a region marked by substantial species-specific variation that likely governs cross-species viral tropism. Together, our structural and biochemical results elucidate the molecular mechanism of substrate recognition and transport by mCAT1, and unveil the molecular basis for FrMLV receptor specificity. These findings provide a valuable framework for structure-based drug design targeting CAT1 in cancer and infectious diseases.

Abstract licence: CC BY-NC-ND