International Journal of Research on Social and Natural Sciences Vol. I Issue 2 December 2016 ISSN (Online) 2455-5916 1 Journal Homepage: www.katwacollegejournal.com Insights into structural features of Plasmodium falciparum 4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase enzyme Achintya Mohan Goswami, Physiology, Krishnagar Government College, West Bengal, India Article Record: Received July 16 2016, Revised paper received Nov. 30 2016, Final Acceptance Dec. 4 2016 Available Online December 7 2016 Abstract Malaria remains one of the most serious infectious diseases in the world. Though there are four species of Plasmodium genus, but the most responsible and virulent among them is Plasmodium falciparum. The unique biochemical processes that exist in Plasmodium falciparum provide a useful way to develop novel inhibitors. One such biochemical pathway is methyl erythritol phosphate (MEP) pathway, required to synthesize isoprenoids. In the present study a detailed computational analysis has been performed for 4-hydroxy-3- methylbut-2-en-1-yl diphosphate synthase, a key enzyme in MEP pathway. The structural properties, secondary structure and evolutionary conservation of the enzyme were studied. The homology model of the enzyme was also developed. Key Words: Plasmodium falciparum; 4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase; Homology modeling; in silico; Methyl erythritol phosphate pathway 1. Introduction Malaria is considered as one of the world’s leading causes of morbidity and mortality as evident from 2016 World Health Organization Report, released in December 2015, “there were 214 million cases of malaria in 2015 and 438,000 deaths” (World Health Organization, 2016). Plasmodium falciparum, a protozoan parasite, is a causative agent of malaria in humans. Malaria caused by this species (also called malignant or falciparum malaria) is the most dangerous form, with the highest rates of complications and mortality. As P. falciparum increasingly develops resistances against commonly used drugs; so identification of novel targets for finding new anti-malarial agents is very important (Rosenthal & Miller, 2001; Daniel et al., 2012). P. falciparum, and other members of the apicomplexa phylum, contains an organelle called the apicoplast. The metabolic pathways in apicoplast differ from the host and therefore apicoplast metabolic pathways open up new possibilities of anti malarial drug designing. The isoprenoid metabolic pathway inside the apicoplast is crucial for the P. falciparum survival (Poulter, 2009). There are two different biosynthetic pathways that have been identified for isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) synthesis. One is the well known mevalonate pathway, which is present in most eukaryotes including mammals, higher plants, and archaea; and the other is methyl erythritol phosphate (MEP) pathway, which occurs in most bacteria, parasitic protozoa of the phylum Apicomplexa, plant plastids, and also present in several pathogenic microorganisms (Rohmer et al., 1993; Eisenreich et al., 2004; Rohmer, 2008; Lombard & Moreira, 2011). The MEP pathway is active in all intra-erythrocytic stages of the parasite and it is not used by humans (van der Meer & Hirsch, 2012). Therefore, this unique targetable pathway may be considered for the development of new drugs against Plasmodium (Jomaa et al., 1999; Wiesner et al., 2008). Enzymes of the MEP pathway have been thoroughly explored in the last 20 years with respect to their molecular and functional properties (Grawert et al., 2011). Recent in silico study with Plasmodium
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International Journal of Research on Social and Natural Sciences Vol. I Issue 2 December 2016 ISSN (Online) 2455-5916
1
Journal Homepage: www.katwacollegejournal.com
Insights into structural features of Plasmodium falciparum
modeling; in silico; Methyl erythritol phosphate pathway
1. Introduction
Malaria is considered as one of the world’s leading causes of morbidity and mortality as evident from 2016 World Health Organization Report, released in December 2015, “there were 214 million cases of malaria in 2015 and 438,000 deaths” (World Health Organization, 2016). Plasmodium
falciparum, a protozoan parasite, is a causative agent of malaria in humans. Malaria caused by this
species (also called malignant or falciparum malaria) is the most dangerous form, with the highest
rates of complications and mortality. As P. falciparum increasingly develops resistances against
commonly used drugs; so identification of novel targets for finding new anti-malarial agents is very
important (Rosenthal & Miller, 2001; Daniel et al., 2012).
P. falciparum, and other members of the apicomplexa phylum, contains an organelle called the
apicoplast. The metabolic pathways in apicoplast differ from the host and therefore apicoplast
metabolic pathways open up new possibilities of anti malarial drug designing. The isoprenoid
metabolic pathway inside the apicoplast is crucial for the P. falciparum survival (Poulter, 2009).
There are two different biosynthetic pathways that have been identified for isopentenyl pyrophosphate
(IPP) and dimethylallyl pyrophosphate (DMAPP) synthesis. One is the well known mevalonate
pathway, which is present in most eukaryotes including mammals, higher plants, and archaea; and the
other is methyl erythritol phosphate (MEP) pathway, which occurs in most bacteria, parasitic protozoa
of the phylum Apicomplexa, plant plastids, and also present in several pathogenic microorganisms
(Rohmer et al., 1993; Eisenreich et al., 2004; Rohmer, 2008; Lombard & Moreira, 2011). The MEP
pathway is active in all intra-erythrocytic stages of the parasite and it is not used by humans (van der
Meer & Hirsch, 2012). Therefore, this unique targetable pathway may be considered for the
development of new drugs against Plasmodium (Jomaa et al., 1999; Wiesner et al., 2008). Enzymes
of the MEP pathway have been thoroughly explored in the last 20 years with respect to their
molecular and functional properties (Grawert et al., 2011). Recent in silico study with Plasmodium
International Journal of Research on Social and Natural Sciences Vol. I Issue 2 December 2016 ISSN (Online) 2455-5916
5
regions in proteins, taking into account the evolutionary relationships among their sequence
homologues (Ramensky et al., 2002). ConSurf was used for high-throughput characterization of the
functional regions of 4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase protein. The
colorimetric conservation grades, projected onto the molecular surface of the 4-hydroxy-3-methylbut-
2-en-1-yl diphosphate synthase, revealed the patches with highly conserved residues that were often
important for biological function (Figure 3). The ConSurf analysis also revealed, as expected, that the
functional regions of the protein were highly conserved. It was observed that from residue 109 to 391
and from 710 to 824 were highly conser
3.3 Protein-protein interaction network of 4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase Protein-protein interaction (PPI) networks have become important for understanding the intricate
molecular mechanisms lying behind the cellular phenomena. The network generation also helps to
design new molecular targets for diseases control.
The protein- protein interacting partners of P. falciparum 4-hydroxy-3-methylbut-2-en-1-yl
diphosphate synthase have been determined by STRING (Figure 4).
During the network prediction, STRING utilizes the reference database of UniProt and predicts
functions of different interacting proteins. PPI network demonstrates that 4-hydroxy-3-methylbut-2-
International Journal of Research on Social and Natural Sciences Vol. I Issue 2 December 2016 ISSN (Online) 2455-5916
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en-1-yl diphosphate synthase interacts with other proteins in a high confidence score; among them are