Novel Highlight in Malarial Drug Discovery: Aspartate Transcarbamoylase

Abstract

Malaria remains one of the most prominent and dangerous tropical diseases. While artemisinin and analogs have been used as first-line drugs for the past decades, due to the high mutational rate and rapid adaptation to the environment of the parasite, it remains urgent to develop new antimalarials. The pyrimidine biosynthesis pathway plays an important role in cell growth and proliferation. Unlike human host cells, the malarial parasite lacks a functional pyrimidine salvage pathway, meaning that RNA and DNA synthesis is highly dependent on the de novo synthesis pathway. Thus, direct or indirect blockage of the pyrimidine biosynthesis pathway can be lethal to the parasite. Aspartate transcarbamoylase (ATCase), catalyzes the second step of the pyrimidine biosynthesis pathway, the condensation of L-aspartate and carbamoyl phosphate to form N-carbamoyl aspartate and inorganic phosphate, and has been demonstrated to be a promising target both for anti-malaria and anti-cancer drug development. This is highlighted by the discovery that at least one of the targets of Torin2 – a potent, yet unselective, antimalarial – is the activity of the parasite transcarbamoylase. Additionally, the recent discovery of an allosteric pocket of the human homology raises the intriguing possibility of species selective ATCase inhibitors. We recently exploited the available crystal structures of the malarial aspartate transcarbamoylase to perform a fragment-based screening to identify hits. In this review, we summarize studies on the structure of Plasmodium falciparum ATCase by focusing on an allosteric pocket that supports the catalytic mechanisms.

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part IV. Plasmodium spp.

“…In his review, Belete [33] claimed that DHODH was inhibited by DSM265, and KAF156 that were evaluated in either phase I or II clinical trials [33] . After identification of the crystal structure of Plasmodium aspartate transcarbamoylase (ATCase), involved in pyrimidine de novo biosynthesis pathway, a review [34] summarized the studies conducted on PfATCase structure. The reviewers aimed to develop allosteric inhibitors with selective binding affinity with its pocket that supports its catalytic mechanisms.…”

“…The reviewers aimed to develop allosteric inhibitors with selective binding affinity with its pocket that supports its catalytic mechanisms. Since PfATCase exists in two distinct states with different substrate affinity, and activity, the reviewers hypothesized that further understanding of the mechanism of PfATCase inhibition would provide an opportunity for novel antimalarial drug development [34] .…”

Actividad antiprotozoaria y antioxidante in vitro de extractos y metabolitos mayoritarios aislados de Pilocarpus alvaradoi (Rutaceae)

“…Actualmente, esta enfermedad está experimentando un resurgimiento y su control se ha convertido en un gran desafío para la salud mundial, además, debido a la alta tasa de mutación del parásito y su rápida adaptación a los cambios ambientales, se están presentando un aumento en la resistencia a los medicamentos y en la distribución geográfica de la enfermedad, lo cual, obliga a realizar esfuerzos continuos hacia la búsqueda y desarrollo de nuevos medicamentos antipalúdicos. (Wang et al, 2022).…”

Malaria therapeutics: are we close enough?

“… 1 Acetyl CoA synthetase It provides acetyl moieties for several metabolic and regulatory cellular pathways, which help in parasite growth [ 42 ] 2 Adenylyl cyclase-β It helps in cyclic adenosine monophosphate (cAMP) synthesis, an essential element of the parasite life cycle [ 43 ] 3 Aminoacyl-tRNA synthetase It helps in the protein synthesis (translation) process by adding an aminoacyl group to the 3’ end of tRNA [ 44 ] 4 Aminopeptidase It is a protease enzyme essential in cell maintenance, cell growth, peptide catabolism (during the asexual erythrocytic replication cycle), protein maturation, antigen presentation on immune cells, and hormone regulation [ 15 ] 5 Anion-exchange protein-1 Involved in erythrocyte invasion (adhesion of infected erythrocytes to endothelial cells) and acid-base homeostasis regulation [ 15 ] 6 Apical membrane antigen-1 Transmembrane protein. It helps parasites invade host erythrocytes [ 15 ] 7 Aspartate aminotransferase It is one of the key enzymes in energy metabolism and de novo biosynthesis of pyrimidines [ 45 ] 8 Aspartate transcarbamoylase It is essential in catalyzing the second step in de novo pyrimidine biosynthesis [ 46 ] 9 ATP synthase Involved in the ATP generation during aerobic glycolysis at the blood stage of the parasite’s life cycle [ 47 ] 10 Calcium-dependent protein kinase-I …”