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Chemical structures of vitamin B6: (a) pyridoxine, (b) pyridoxal, (c) pyridoxamine, and (d) its active form pyridoxal 5-phosphate.
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Malaria is a deadly infectious disease which affects millions of people each year in tropical regions. There is no effective vaccine available and the treatment is based on drugs which are currently facing an emergence of drug resistance and in this sense the search for new drug targets is indispensable. It is well established that vitamin biosynth...
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Whereas studies have extensively examined the ability of bacteria to influence Plasmodium infection in the mosquito, the tripartite interactions between non-entomopathogenic fungi, mosquitoes, and Plasmodium parasites remain largely uncharacterized. Here we report the isolation of a common mosquito-associated ascomycete fungus, Penicillium chrysoge...
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... Serine hydroxyl methyltransferase (SHMT) is an enzyme that plays a crucial role in the metabolism of P. falciparum, the parasite responsible for causing malaria in humans. This enzyme is involved in several metabolic pathways within the parasite, contributing to its survival and growth [11]. Due to its central role in folate metabolism, SHMT has been explored as a potential drug target for the treatment of malaria. ...
The present study aimed to analyze the artemisinin content in various extracts of Artemisia annua L. using a validated HPTLC densitometry method and evaluate the inhibitory activity of artemisinin against serine hydroxyl methyltransferase (SHMT) of Plasmodium falciparum using in silico approach. High performance thin layer chromatography revealed that the petroleum ether extract of A. annua had the highest artemisinin content (0.71% ± 0.02 w/w), methanol extract (0.25% ± 0.02 w/w), chloroform extract (0.14% ± 0.01 w/w), and water extract (0.06% ± 0.01 w/w). Densitometry result indicated a well-defined and symmetrical peak in the petroleum ether extract, indicating excellent separation of high-purity artemisinin. In silico study of artemisinin with SHMT enzyme portrayed an excellent binding affinity (-9.1 kcal/mol) and convenient interactions compared with control. Moreover, both artemisinin and control compound showed good absorption, distribution, metabolism, excretion and toxicity properties. In conclusion, the study suggested that the petroleum ether extract of A. annua is the most suitable and efficient solvent for extracting high-quantity artemisinin. The findings of the molecular docking analysis further supported the potential inhibitory activity of artemisinin against the SHTM of P. falciparum. This research contributes to the understanding of artemisinin's antimalarial properties and optimized method of its production efficiently.
... Previous studies in P. vivax metabolomics have identified various metabolic pathways including xenobiotics, glycosphingolipids, aspartate and asparagine, purine and pyrimidine, vitamin B6, methionine and cysteine, fatty acid, urea cycle, stearoylcarnitine, phosphocholine, glycerophosphocholine, biliverdin, bilirubin, palmitoylcarnitine, oleic acid and omega-carboxytrinor-leukotriene B4 metabolism 5,12,22,27,28 . Additionally, important biomarkers like plasmodial lactate dehydrogenase, histidine-rich protein II, and urinary ornithine have been identified 22,29,30 . ...
... Pyridoxal 5-phosphate, the active form of vitamin B6, acts as a cofactor for several crucial enzymes found in the metabolism of Plasmodium sp., playing a role in protein biosynthesis, and in serine hydroxymethyltransferase (SHMT), a key enzyme in folate metabolism. This result confirmed that the vitamin B6 biosynthetic pathway is an excellent drug target 27 . Tryptophan metabolism alteration in the non-recurrent participants occurs because malaria parasite relies on the host's tryptophan as a crucial nutrient source for its survival and growth 59 . ...
Malaria is the leading parasitic disease worldwide, with P. vivax being a major challenge for its control. Several studies have indicated metabolomics as a promising tool for combating the disease. The study evaluated plasma metabolomic profiles of patients with recurrent and non-recurrent P. vivax malaria in the Brazilian Amazon. Metabolites extracted from the plasma of P. vivax-infected patients were subjected to LC–MS analysis. Untargeted metabolomics was applied to investigate the metabolic profile of the plasma in the two groups. Overall, 51 recurrent and 59 non-recurrent patients were included in the study. Longitudinal metabolomic analysis revealed 52 and 37 significant metabolite features from the recurrent and non-recurrent participants, respectively. Recurrence was associated with disturbances in eicosanoid metabolism. Comparison between groups suggest alterations in vitamin B6 (pyridoxine) metabolism, tyrosine metabolism, 3-oxo-10-octadecatrienoate β-oxidation, and alkaloid biosynthesis II. Integrative network analysis revealed enrichment of other metabolic pathways for the recurrent phenotype, including the butanoate metabolism, aspartate and asparagine metabolism, and N-glycan biosynthesis. The metabolites and metabolic pathways predicted in our study suggest potential biomarkers of recurrence and provide insights into targets for antimalarial development against P. vivax.
... Inhibitors of PK are regarded as promising drug candidates for the treatment of protozoan infectious illnesses because these drug targets play a crucial role in vitamin B6 metabolism in cells (Jones et al., 2012;Oliveira-da-Silva et al., 2020). In the cases of Trypanosoma brucei and Plasmodium falciparum, PK has been identified as a potential drug target due to its essential role in the survival and pathogenicity of the parasites (Kronenberger et al., 2014). Various investigations focused on leishmanial PK have asserted its ability to impede the propagation of infection and the proliferation of the pathogen Kumar et al., 2018). ...
Leishmania donovani, an obligatory intracellular flagellate pathogen, is the underlying cause of visceral leishmaniasis (VL), a fatal disease that poses a significant challenge to existing therapeutic approaches and leads to human mortality. In an endeavor to find an antileishmanial drug to combat VL, we aimed to assess the approved drug molecules against the specific drug targets of VL. In this study, a theoretical method was used to select two essential therapeutic targets (pyridoxal kinase [PK] and sterol alpha-14 demethylase [SDM]) which were present in both the data set of essential genes and drug target proteins. The selected PK and SDM proteins in L. donovani play pivotal roles as essential enzymes in the crucial vitamin B6 salvage and sterol biosynthesis pathways, respectively, leading to pathogenicity in humans. In addition to that drugs were gathered from the DrugBank and Drug Central databases and 325 (out of 4867) compounds having anti-parasitic properties were screened by PASS analysis. Consequently, three ligands (referred to as Lig_1, Lig_2, and Lig_3) were chosen based on their elevated Pa values, docking scores, and notable medicinal applications. Moreover, the result obtained from MD simulation suggests Lig_1 [Nitazoxanide (PubChem ID-41684)] does not affect the structural integrity of both targets. Additionally, evaluation of total binding energies by MMPBSA analysis showed stronger binding of Lig_1 with PK and SDM is -100.71 and -175.61 kJ/mol, respectively compared to others. As a whole, the methodology employed in this research involves the simultaneous identification of suitable protein targets and potential inhibitors. Through this investigation, we have demonstrated that compounds derived from a biocomputing approach exhibit interaction mechanisms as inhibitors against drug targets, offering a promising avenue for addressing VL.
... This activity, in conjunction with its impressive antimalarial activity, makes riboflavin attractive as a safe and inexpensive drug for treating malaria caused by P. falciparum [99]. The active form of vitamin B6, pyridoxal 5-phosphate, is, besides its antioxidative properties, a cofactor for a variety of essential enzymes present in the malaria parasite which includes the ornithine decarboxylase (ODC, synthesis of polyamines), the aspartate aminotransferase (AspAT, involved in the protein biosynthesis), and the serine hydroxymethyltransferase (SHMT, a key enzyme within the folate metabolism) [100]. ...
... The classical role of PLP involves its electrophilic stabilizer effect of the carbanion in several enzymatic reactions. The PLP-dependent enzymes can be classified into seven groups, according to the enzyme activity: (i) aminotransferases and the amino-acid decarboxylases, such as serino hydroxymethyltransferases and aspartate aminotransferases; (ii) activity on the replacement and elimination of Cb groups, such as serine and threonine dehydratases; (iii) activity on the interconversion of L-and Damino acids with a common fold (a/b) 8 , such as alanine racemase; (iv) alanine aminotransferase; (v) glycogen phosphorylase; (vi) 5,6-aminomutase; and (vii) 2,3aminomutase (Kronenberger et al., 2014). In Plasmodium, most of the PLP-dependent enzymes are classified in groups 1 and 2, highlighting their relevance in amino acid metabolism (Kappes et al., 2011;Kronenberger et al., 2014). ...
... The PLP-dependent enzymes can be classified into seven groups, according to the enzyme activity: (i) aminotransferases and the amino-acid decarboxylases, such as serino hydroxymethyltransferases and aspartate aminotransferases; (ii) activity on the replacement and elimination of Cb groups, such as serine and threonine dehydratases; (iii) activity on the interconversion of L-and Damino acids with a common fold (a/b) 8 , such as alanine racemase; (iv) alanine aminotransferase; (v) glycogen phosphorylase; (vi) 5,6-aminomutase; and (vii) 2,3aminomutase (Kronenberger et al., 2014). In Plasmodium, most of the PLP-dependent enzymes are classified in groups 1 and 2, highlighting their relevance in amino acid metabolism (Kappes et al., 2011;Kronenberger et al., 2014). A second role of PLP in Plasmodium involves the protection of the parasite against singlet oxygen ( 1 O 2 ). ...
Malaria is still today one of the most concerning diseases, with 219 million infections in 2019, most of them in Sub-Saharan Africa and Latin America, causing approx. 409,000 deaths per year. Despite the tremendous advances in malaria treatment and prevention, there is still no vaccine for this disease yet available and the increasing parasite resistance to already existing drugs is becoming an alarming issue globally. In this context, several potential targets for the development of new drug candidates have been proposed and, among those, the de novo biosynthesis pathway for the B6 vitamin was identified to be a promising candidate. The reason behind its significance is the absence of the pathway in humans and its essential presence in the metabolism of major pathogenic organisms. The pathway consists of two enzymes i.e. Pdx1 (PLP synthase domain) and Pdx2 (glutaminase domain), the last constituting a transient and dynamic complex with Pdx1 as the prime player and harboring the catalytic center. In this review, we discuss the structural biology of Pdx1 and Pdx2, together with and the understanding of the PLP biosynthesis provided by the crystallographic data. We also highlight the existing evidence of the effect of PLP synthesis inhibition on parasite proliferation. The existing data provide a flourishing environment for the structure-based design and optimization of new substrate analogs that could serve as inhibitors or even suicide inhibitors.
... On the other hand, some other pathogenic organisms, including organisms with high antibiotic resistance rates, have already been identified as susceptible to modulations of the pyridoxal phosphate biosynthesis pathway. Some organisms that have been the focus of basic research include P. falciparum and Plasmodium vivax, the malaria pathogens (45)(46)(47)(48). ...
Antibiotic resistance is a worldwide concern that requires a concerted action from physicians, patients, governmental agencies, and academia to prevent infections and the spread of resistance, track resistant bacteria, improve the use of current antibiotics, and develop new antibiotics. Despite the efforts spent so far, the current antibiotics in the market are restricted to only five general targets/pathways highlighting the need for basic research focusing on the discovery and evaluation of new potential targets. Here we interrogate two biosynthetic pathways as potentially druggable pathways in bacteria. The biosynthesis pathway for thiamine (vitamin B1), absent in humans, but found in many bacteria, including organisms in the group of the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter sp.) and the biosynthesis pathway for pyridoxal 5′-phosphate and its vitamers (vitamin B6), found in S. aureus. Using current genomic data, we discuss the possibilities of inhibition of enzymes in the pathway and review the current state of the art in the scientific literature.
... Similarly, the knockout study of PdxK from a related parasite, Trypanosoma brucei has shown this enzyme to be vital for the parasitic survival and infection [16]. Simultaneously, PdxK from Plasmodium falciparum has been employed as a drug target by funneling prodrugs into metabolism of the parasite [17]. Anti-malarial compounds, chloroquine and primaquine had shown inhibitory activity against pyridoxal kinase [18]. ...
... In E.coli, Ser47 and Gly48 are replaced by Pro58 and His59/Gln46 residues, respectively, in the loop II. Structural comparison of LdPdxK with PdxKs from E. coli has shown that Gly48 is replaced by bulky side chain residues; His in E. coli PdxK1 and Gln in E. coli PdxK2 [16,17] covering the active site from the bulky solvent and in the C4′ position of the substrate. Replacement of His or Gln with Gly in LdPdxK like sheep PdxK [32], leaves the C4′ position accessible to the bulky solvent that explains the tolerance of this enzyme for different substituents at the C4′ position of the substrate compared to prokaryotes [65]. ...
The enzyme pyridoxal kinase (PdxK) catalyzes the conversion of pyridoxal to pyridoxal-5'-phosphate using ATP as the co-factor. The product pyridoxal-5'-phosphate (PLP) plays a key role in several biological processes such as transamination, decarboxylation and deamination. In the present study, full-length ORF of PdxK from Leishmania donovani (LdPdxK) was cloned and then purified using affinity chromatography. LdPdxK exists as a homo-dimer in solution and shows more activity at near to physiological pH. Biochemical analysis of LdPdxK with pyridoxal, pyridoxamine, pyridoxine and ginkgotoxin revealed its affinity preference towards different substrates. The secondary structure analysis using circular dichroism spectroscopy showed LdPdxK to be predominantly α-helical in organization which tends to decline at lower and higher pH. Simultaneously, LdPdxK was crystallized and its three dimensional structure in complex with ADP and different substrates were determined. Crystal structure of LdPdxK delineated that it has a central core of β-sheets surrounded by α-helices with a conserved GTGD ribokinase motif. The structures of LdPdxK disclosed no major structural changes between ADP and ADP- substrate bound structures. In addition, comparative structural analyses highlighted the key differences between the active site pockets of leishmanial and human PdxK, rendering LdPdxK an attractive candidate for the designing of novel and specific inhibitors.
... The two genes (encoding for PDX1 and PDX2) are expressed throughout the intraerythrocytic and gametocyte development and have been explored as potential drug targets (74 -77). Prodrugs such as pyridoxyl-tryptophan chimeras that interfere with PLP-dependent enzymes and poison the parasite have also been investigated as antimalarials (78,79). For organisms that lack biosynthesis capabilities, identification of the transporter of pyridoxal and its derivatives would be of significant interest. ...
The Apicomplexa phylum comprises diverse parasitic organisms that have evolved from a free-living ancestor. These obligate intracellular parasites exhibit versatile metabolic capabilities reflecting their capacity to survive and grow in different hosts and varying niches. Determined by nutrient availability, they either use their biosynthesis machineries or largely depend on their host for metabolite acquisition. Because vitamins cannot be synthesized by the mammalian host, the enzymes required for their synthesis in apicomplexan parasites represent a large repertoire of potential therapeutic targets. Here, we review recent advances in metabolic reconstruction and functional studies coupled to metabolomics that unravel the interplay between biosynthesis and salvage of vitamins and cofactors in apicomplexans. A particular emphasis is placed on Toxoplasma gondii, during both its acute and latent stages of infection.
... The two genes (PDX1 and PDX2) are expressed throughout the intraerythrocytic and gametocyte development and have been explored as potential drug targets (77)(78)(79)(80). Prodrugs such as pyridoxyl-tryptophan chimeras that interfere with PLP-dependent enzymes and poison the parasite have also been investigated as antimalarials (81,82). For organisms that lack biosynthesis capabilities, identification of the transporter of pyridoxal and its derivatives would be of significant interest. ...
The Apicomplexa phylum comprises diverse parasitic organisms that have evolved from a free-living ancestor. These obligate intracellular parasites exhibit versatile metabolic capabilities reflecting their capacity to survive and grow in different hosts and varying niches. Determined by nutrient availability, they either use their biosynthesis machineries or largely depend on their host for metabolite acquisition. Since vitamins cannot be synthesized by the mammalian host, the enzymes required for their synthesis in apicomplexan parasites represent a large repertoire of potential therapeutic targets. Here, we review recent advances in metabolic reconstruction and functional studies coupled to metabolomics that unravel the interplay between biosynthesis and salvage of vitamins and cofactors in apicomplexans. A particular emphasis is placed on Toxoplasma gondii, during both its acute and latent stages of infection.
... On the other hand, some other pathogenic organisms, including organisms with high antibiotic resistance rates, have already been identified as susceptible to modulations of the pyridoxal phosphate biosynthesis pathway. Some organisms which have been the focus of basic research include Plasmodium falciparum and Plasmodium vivax, the malaria pathogens (35)(36)(37)(38). ...
The antibiotic resistance is a worldwide concern and that requires a concerted action from physicians, patients, governmental agencies and academia to prevent infections and the spread of resistance, to track resistant bacteria, to improve the use of current antibiotics and to develop new antibiotics. Despite the efforts spent so far, the current antibiotics in the market are restricted to only five general targets/pathways highlighting the need for basic research focusing on the discovery and evaluation of new potential targets. Here we interrogate two biosynthetic pathways as potentially druggable pathways in bacteria. The biosynthesis pathway for thiamine (vitamin B1), absent in humans, but found in many bacteria, including pathogenic organism in the group of the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa and Enterobacter species) and the biosynthesis pathway for pyridoxal 5'-phosphate and its vitamers (vitamin B6), found in S. aureus. Using current genomic data, we discuss the possibilities of inhibition of enzymes in the pathway and review the current state of the art in the scientific literature.
