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The Apicomplexa phylum encompasses numerous obligate intracellular parasites, some associated with severe implications for human health, including Plasmodium, Cryptosporidium, and Toxoplasma gondii. The iron-sulfur cluster [Fe-S] biogenesis ISC pathway, localized within the mitochondrion or mitosome of these parasites, is vital for parasite survival and development. Previous work on T. gondii and Plasmodium falciparum provided insights into the mechanisms of [Fe-S] biogenesis within this phylum, while the transporter linking mitochondria-generated [Fe-S] with the cytosolic [Fe-S] assembly (CIA) pathway remained elusive. This critical step is catalyzed by a well-conserved ABC transporter, termed ATM1 in yeast, ATM3 in plants and ABCB7 in mammals. Here, we identify and characterize this transporter in two clinically relevant Apicomplexa. We demonstrate that depletion of TgATM1 does not specifically impair mitochondrial metabolism. Instead, proteomic analyses reveal that TgATM1 expression levels inversely correlate with the abundance of proteins that participate in the transfer of [Fe-S] to cytosolic proteins at the outer mitochondrial membrane. Further insights into the role of TgATM1 are gained through functional complementation with the well-characterized yeast homolog. Biochemical characterization of PfATM1 confirms its role as a functional ABC transporter, modulated by oxidized glutathione (GSSG) and [4Fe-4S]. Author summary: The Apicomplexa phylum includes harmful parasites like Plasmodium falciparum and Toxoplasma gondii, posing significant threats to human health. Understanding their survival mechanisms is crucial for developing effective treatments. Here, our focus is on iron-sulfur cluster [Fe-S] synthesis pathways found in the mitochondrion and cytosol, essential for the function of many enzymes. Although the transporter responsible for moving sulfur-containing compounds from mitochondria to the cytosol is known in other organisms, it remains unidentified in apicomplexans. Our study identifies PfATM1 and TgATM1 as critical transporters in the mitochondrial membrane of these parasites. Downregulation or overexpression of TgATM1 levels do not hinder mitochondrial functions but affect the level of other proteins, suspected to donate [Fe-S] to cytosolic proteins. We further confirm the transporter's role by rescuing TgATM1 depleted parasites with the yeast homolog ScATM1. Additionally, we identify glutathione-coordinated [4Fe-4S] as a probable substrate for PfATM1. These findings provide valuable insights into how parasites manage essential resources, potentially opening new avenues for targeted drug development. [ABSTRACT FROM AUTHOR]

Abstract: This study describes the isolation and purification of a phytocystatin from seeds of Brassica juncea (Indian mustard; cultivar RoAgro 5444), which is an important oilseed crop both agriculturally and [...]

Nicotinamide N-methyltransferase (NNMT) is a protein coding gene, which methylates the nicotinamide (NA) (vitamin B3) to produce 1-methylnicotinamide (MNA). Several studies have suggested that the overexpression of NNMT is associated with different metabolic disorders like obesity and type-2 diabetes thereby making it an important therapeutic target for development of anti-diabetic agents. Here we describe a workflow for identification of new inhibitors of NNMT from a library of small molecules. In this study, we have hypothesized a four-point pharmacophore model based on the pharmacophoric features of reported NNMT inhibitors in the literature. The statistically significant pharmacophore hypothesis was used to explore the Maybridge compound library that resulted in mapping of 1330 hit compounds on the proposed hypothesis. Subsequently, a total of eight high scoring compounds, showing good protein–ligand interactions in the molecular docking study, were selected for biological evaluation of NNMT activity. Eventually, four compounds were found to show significant inhibitory activity for NNMT and can be further explored to design new derivatives around the identified scaffolds with improved activities as NNMT inhibitors. [ABSTRACT FROM AUTHOR]