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Review
. 2019 Oct 16;24(20):3721.
doi: 10.3390/molecules24203721.

Prenylquinones in Human Parasitic Protozoa: Biosynthesis, Physiological Functions, and Potential as Chemotherapeutic Targets

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Free PMC article
Review

Prenylquinones in Human Parasitic Protozoa: Biosynthesis, Physiological Functions, and Potential as Chemotherapeutic Targets

Ignasi B Verdaguer et al. Molecules. .
Free PMC article

Abstract

Human parasitic protozoa cause a large number of diseases worldwide and, for some of these diseases, there are no effective treatments to date, and drug resistance has been observed. For these reasons, the discovery of new etiological treatments is necessary. In this sense, parasitic metabolic pathways that are absent in vertebrate hosts would be interesting research candidates for the identification of new drug targets. Most likely due to the protozoa variability, uncertain phylogenetic origin, endosymbiotic events, and evolutionary pressure for adaptation to adverse environments, a surprising variety of prenylquinones can be found within these organisms. These compounds are involved in essential metabolic reactions in organisms, for example, prevention of lipoperoxidation, participation in the mitochondrial respiratory chain or as enzymatic cofactors. This review will describe several prenylquinones that have been previously characterized in human pathogenic protozoa. Among all existing prenylquinones, this review is focused on ubiquinone, menaquinone, tocopherols, chlorobiumquinone, and thermoplasmaquinone. This review will also discuss the biosynthesis of prenylquinones, starting from the isoprenic side chains to the aromatic head group precursors. The isoprenic side chain biosynthesis maybe come from mevalonate or non-mevalonate pathways as well as leucine dependent pathways for isoprenoid biosynthesis. Finally, the isoprenic chains elongation and prenylquinone aromatic precursors origins from amino acid degradation or the shikimate pathway is reviewed. The phylogenetic distribution and what is known about the biological functions of these compounds among species will be described, as will the therapeutic strategies associated with prenylquinone metabolism in protozoan parasites.

Keywords: drug targets; neglected diseases; parasitic protozoa; phylogeny; prenylquinones.

Conflict of interest statement

All authors certify that they have NO conflicts of interest.

Figures

Figure 1
Figure 1
The chemical structures of prenylquinones. The figure shows the chemical structures of prenylquinones already characterized in pathogenic protozoa. n indicates the variable related to the isoprenic units contained on the prenylquinone side chain. Structures designed using ACD/ChemSketch, version 12, Advanced Chemistry Development, Inc., Toronto, ON, Canada.
Figure 2
Figure 2
Scheme of chorismate synthesis from aromatic amino acids (tyrosine and phenylalanine) or the shikimate pathway. DAHP; PEP; TAT/ASAT (EC 2.6.1.5); HRPR (EC 1.1.1.237); U.E. (uncharacterized enzyme); 4CL (EC 6.2.1.12); HBAT (EC 3.1.2.23); CL (EC 4.1.3.40); PDH (EC 1.3.1.12/1.3.1.13); PDT (EC 4.2.1.51); CM (EC 5.4.99.5); DAHPS (EC 2.5.1.54); DHQS (EC 4.2.3.4); DHQD (EC 4.2.1.10); SDH (EC 1.1.1.25/1.1.5.8/1.1.1.282); SK (EC 2.7.1.71); EPSPS (EC 2.5.1.19); CS (EC 4.2.3.5). Based on information from Kyoto Encyclopedia of Genes and Genomes database [87].
Figure 3
Figure 3
Scheme of isoprenoid biosynthesis up to isopentenyl pyrophosphate (IPP). The dotted, red arrow indicates the hypothetical IPP Biosynthesis Pathway previously mentioned in the text, starting from intermediate metabolites of the pentose phosphate pathway in Synechocystis sp. and a possibility that has not been investigated to date in any pathogenic protozoan [70]. BCAT/LeuT/LeuDH (EC 2.6.1.42/2.6.1.6/1.4.1.9); BCKADH/VOR complex (EC 1.2.4.4, 2.3.1.168, 1.8.1.4/1.2.7); IVD/ACADM (EC 1.3.8.4/1.3.8.7); MCCase (EC 6.4.1.4); MGCH (EC 4.2.1.18); HMGS (EC 2.3.3.10); HMGR (EC 1.1.1.34/1.1.1.88); MVK (EC 2.7.1.36); PMK (EC 2.7.4.2); MVD (EC 4.1.1.33); DXS (EC 2.2.1.7); DXR (EC 1.1.1.267); IspD (EC 2.7.7.60); IspE (EC 2.7.1.148); IspF (EC 4.6.1.12); IspG (EC 1.17.7.1/1.17.7.3); IspH (EC 1.17.7.4) Based on information from Kyoto Encyclopedia of Genes and Genomes database [87].
Figure 4
Figure 4
Isoprenic chain elongation/reduction. Isoprenic chain chemical structures and its elongation/reduction pathways. Continuous arrows indicate a single enzymatic step and discontinuous arrows indicate several enzymatic steps. Enzymatic steps are better described in the text. Structures sourced from Kyoto Encyclopedia of Genes and Genomes database [87].
Figure 5
Figure 5
Prenylquinone biosynthesis pathways [45]. Some prenylquinones shown have not been found in pathogenic protozoa, but all are cited in this review. The specific pathway of ubiquinone biosynthesis (orange arrows) and the formation of aromatic precursors from amino acid metabolism/shikimate pathways (gray arrows) are simplified because these processes are better described in other figures in this review. The incorporation of isoprene chains and use of S-adenosyl-L-methionine (SAM) by enzymes are indicated. The SAM cofactor is necessary for methylation reactions to produce S-adenosyl homocysteine or for other biochemical processes. Continuous arrows indicate a single enzymatic step, and discontinuous arrows indicate several enzymatic steps, processes that remain poorly understood or processes that are better shown in other figures in this review. The different pathways are distinguishable by the colors of the arrows: Light purple. MQ biosynthesis by the futalosine alternative pathway; Dark blue. Homologous enzymatic steps that are common for PK or MQ biosynthesis by the classic pathway; Dark purple. Specific enzymatic steps for MQ biosynthesis by the classic pathway; Light blue. Enzymatic steps that are specific for PK biosynthesis; Black. Biosynthesis of homogentisate from 4-hydroxyphenylpyruvate; Dark green. Tocopherol biosynthesis [142]; Light green. Shared enzymatic steps for PQ and plastochromanol biosynthesis; Yellow. Plastochromanol biosynthesis [45]; Brown. 4-Hydroxybenzoate biosynthesis from chorismate; Orange. Ubiquinone biosynthesis; Red. Possible rhodoquinone biosynthesis pathway in Rhodospirillum rubrum [143]. The figure also indicates processes that remain poorly understood. ?A. The final steps of the futalosine alternative pathway [144]; ?B. Biosynthesis of MQ derivatives such as ChQ or sulfated MQs (among other examples) [45]; ?C. α-Tocopherol biosynthesis from β-tocopherol; ?D. 2-Methyl-6-solanesyl-1,4-benzoquinol biosynthesis from 4-hydroxy-3-polyprenylbenzoate in cyanobacteria [145]; ?E. The formation of some PQ derivatives (e.g., PQ-B, PQ-C) is controversial in the literature [45]; ?F. Rhodoquinone biosynthesis requires ubiquinone in Rhodospirillum rubrum [143], but the process remains poorly understood. Next to each arrow, the corresponding enzyme is cited. For biosynthesis of tocopherol, plastochromanol and PQ, different enzymes can perform the same enzymatic step depending on the organism [141]. Enzymes: MqnA (chorismate dehydratase, EC:4.2.1.151). MqnE. (aminodeoxyfutalosine synthase, EC:2.5.1.120). ADD (aminodeoxyfutalosine deaminase, EC:3.5.4.40). MqnB (futalosine hydrolase, EC:3.2.2.26). MqnC (cyclic dehypoxanthinyl futalosine synthase, EC:1.21.98.1). MqnD (EC 1.14.). MenF (EC 5.4.4.2). MenD (EC 2.2.1.9). MenH (EC 4.2.99.20). MenC (EC 4.2.1.113). MenE (EC 6.2.1.26). MenB (EC 4.1.3.36). DHNA-CoA (EC 3.1.2.28). MenA (EC 2.5.1.74). MenG/UbiE (demethylmenaquinone methyltransferase/2-methoxy-6-polyprenyl-1,4-benzoquinol methylase; EC:2.1.1.163/EC:2.1.1.201, respectively). HPPD (EC:1.13.11.27). HPT (homogentisate phytyltransferase/homogentisate geranylgeranyltransferase; EC:2.5.1.115/EC:2.5.1.116, respectively). VTE3/APG1 (EC 2.1.1.295). VTE1/DXD1 (EC 5.5.1.24). VTE4/α-TMT (EC 2.1.1.95). HST (EC 2.5.1.117). UbiC (EC 4.1.3.40). UbiA (EC 2.5.1.39). Based on information from the cited references in the text and the Kyoto Encyclopedia of Genes and Genomes database [87].
Figure 6
Figure 6
Chemical structures of ubiquinone and atovaquone. (a) Chemical structures of UQ, n indicates variable number of isoprenic units contained on the prenylquinone side chain. (b) The antiparasitic drug atovaquone.
Figure 7
Figure 7
Scheme of ubiquinone biosynthesis. UQ biosynthesis from 4-hydroxybenzoate. In the figure depicting the metabolic pathways, the transformation of the cofactor SAM to S-adenosyl-l-homocysteine (SAH) for methylation is indicated. UbiC. Chorismate-pyruvate lyase, EC: 4.1.3.40; UbiA/Coq2. EC: 4-Hydroxybenzoate polyprenyltransferase, 2.5.1.39; UbiD. 4-Hydroxy-3-polyprenylbenzoate decarboxylase, EC: 4.1.1.98; Coq7/UbiI. 2-Polyprenylphenol 6-hydroxylase, EC: 1.14.13.240; UbiH/Coq6. UQ biosynthesis monooxygenase/2-octaprenyl-6-methoxyphenol hydroxylase, EC: 1.14.13.-; UbiE/Coq5. 2-Methoxy-6-polyprenyl-1,4-benzoquinol methylase, EC: 2.1.1.201; UbiF/Coq7. 3-Demethoxyubiquinol 3-hydroxylase, EC: 1.14.99.60; UbiG/Coq3. Polyprenyldihydroxybenzoate methyltransferase/3-demethylubiquinol, 3-O-methyltransferase/2-polyprenyl-6-hydroxyphenyl methylase/3-demethylubiquinone-9 3-methyltransferase, EC: 2.1.1.114/2.1.1.64/2.1.1.222/. Data from the Kyoto Encyclopedia of Genes and Genomes database [87].
Figure 8
Figure 8
Chemical structures of tocopherols. (a) Chemical structures of alpha-tocopherol, (b) beta-tocopherol, (c) gamma-tocopherol and (d) delta-tocopherol.

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