cis-Prenyltransferase: New Insights into Protein Glycosylation, Rubber Synthesis, and Human Diseases

doi:10.1074/jbc.R116.739490

Review

. 2016 Aug 26;291(35):18582-90.

doi: 10.1074/jbc.R116.739490. Epub 2016 Jul 11.

cis-Prenyltransferase: New Insights into Protein Glycosylation, Rubber Synthesis, and Human Diseases

Kariona A Grabińska¹, Eon Joo Park¹, William C Sessa²

Affiliations

¹ From the Department of Pharmacology and Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520.
² From the Department of Pharmacology and Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520 [email protected].

PMID: 27402831
PMCID: PMC5000101
DOI: 10.1074/jbc.R116.739490

Review

cis-Prenyltransferase: New Insights into Protein Glycosylation, Rubber Synthesis, and Human Diseases

Kariona A Grabińska et al. J Biol Chem. 2016.

. 2016 Aug 26;291(35):18582-90.

doi: 10.1074/jbc.R116.739490. Epub 2016 Jul 11.

Authors

Kariona A Grabińska¹, Eon Joo Park¹, William C Sessa²

Affiliations

¹ From the Department of Pharmacology and Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520.
² From the Department of Pharmacology and Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520 [email protected].

PMID: 27402831
PMCID: PMC5000101
DOI: 10.1074/jbc.R116.739490

Abstract

cis-Prenyltransferases (cis-PTs) constitute a large family of enzymes conserved during evolution and present in all domains of life. cis-PTs catalyze consecutive condensation reactions of allylic diphosphate acceptor with isopentenyl diphosphate (IPP) in the cis (Z) configuration to generate linear polyprenyl diphosphate. The chain lengths of isoprenoid carbon skeletons vary widely from neryl pyrophosphate (C10) to natural rubber (C>10,000). The homo-dimeric bacterial enzyme, undecaprenyl diphosphate synthase (UPPS), has been structurally and mechanistically characterized in great detail and serves as a model for understanding the mode of action of eukaryotic cis-PTs. However, recent experiments have revealed that mammals, fungal, and long-chain plant cis-PTs are heteromeric enzymes composed of two distantly related subunits. In this review, the classification, function, and evolution of cis-PTs will be discussed with a special emphasis on the role of the newly described NgBR/Nus1 subunit and its plants' orthologs as essential, structural components of the cis-PTs activity.

Keywords: DHDDS; NUS1; NgBR; RER2; cis-prenyltransferase; dolichol; enzyme; genetic disease; glycosylation; glycosylphosphatidylinositol (GPI anchor); hCIT; lipid; polyprenol; polyprenol synthesis.

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Figures

**FIGURE 1.**
**The role *cis*-PTs in dolichol phosphate synthesis and protein glycosylation.** A, DolP synthesis *de novo* in eukaryotic cell. Genes encoding enzymes involved in DolP synthesis in human cell are marked in *red. DOLK*, dolichol kinase. B, the role of heteromeric *cis*-PT in protein glycosylation. *cis*-PT generates polyprenol diphosphate on the cytoplasmic leaflet of the ER membrane. Polyprenol diphosphate is used as an intermediate in the synthesis of dolichol-linked saccharides (*LLO*). LLO is intermediate in protein N-glycosylation reactions. Dolichol-phosphate mannose (*DolPMan*) is also involved in O-mannosylation, glycosylphosphatidylinositol (*GPI*) anchor synthesis, and C-mannosylation. *DolPGlc*, dolichol-phosphate glucose; *circled P*, phosphorylation.

**FIGURE 2.**
**Classification of *cis*-prenyltransferases.** A, classification of *cis*-PTs according to product chain length and subunit structure. *Gray lines* indicate numbers of isoprene units of representative allylic substrates for each *cis*-PT. *Red arrow*s indicate numbers of isoprene units of representative final products. Enzymes represented in the figure are: SlCPT1 (*Solanum lycopersicum*, GenBank^TM NM_001247704), Rv1086 (*M. tuberculosis*, GenBank: CFB23420.1), SlCPT2 (*S. lycopersicum* GenBank JX943884), AtCPT6 (*A. thaliana*, GenBank NP_568882), Rv2361c (*M. tuberculosis*, GenBank: WP_031739650), EcUPPS (*Escherichia coli*, GenBank: P60472), SaUPPS (*Sulfolobus acidocaldarius*, GenBank WP_011277635.1), SlCPT3/SlCPTBP (*S. lycopersicum* GenBank: JX943885/XP_004241992), hCIT/NgBR (*Homo sapiens* GenBank accession NP_612468/BAB14439), *RER2/NUS1* (*S. cerevisiae*, GenBank P35196/NP_010088), TbRTA/CPT1–3 (*T. brevicorniculatum*, GenBank ALX37963/AGE89403/AGE89404/AGE89405), and LsCPTL2/LsCPT3 (*L. sativa*, GenBank AIQ81190/AIQ81186). B, alignment of the C terminus of NgBR orthologs (hNgBR, human; mNgBR, mouse; SpNus1, *S. pombe*; ScNus1, *S. cerevisiae*; AtLEW1, *A. thaliana*) and single subunit *cis*-PTs (MlUPPS, *Micrococcus luteus*; MtDPPS, *M. tuberculosis*; EcUPPS, *E. coli*; PaUPPS, *P. aeruginosa*; GlcisPT, *G. lamblia*; and MfUPPS, *Methanobacterium formicicum*). The conservation scoring was performed by PRALINE. The scoring scheme works from 0 for the least conserved alignment position, up to 10 (*) for the most conserved alignment position.

**FIGURE 3.**
**Phylogenetic distribution of known and predicted single-component *cis*-PTs and hCIT/Rer2 orthologs from animals, plants and microbes.** The evolutionary history was inferred using the neighbor-joining method and conducted in MEGA7(90). Species abbreviations are: Ao, *Aspergillus oryzae*; Ap, *Auxenochlorella protothecoides*; At, *A. thaliana*; Av, *Archaeoglobus veneficus*; Ca, *Candida albicans*; Ce, *Caenorhabditis elegans*; Df, *Dictyostelium fasciculatum*; Dm, *Drosophila melanogaster*; Dr, *Danio rerio*; Ec, *E. coli*; Gg, *Gallus gallus*; Gl, *G. lamblia*; Hb, *Halogeometricum borinquense*; Hm, *Haloferax mediterranei*; Hs, *H. sapiens*; Kc, *Korarchaeum cryptofilum*; Lc, *L. sativa*; Lm, *Leishmania major*; *Loki*, *Lokiarchaeum* sp.; Ma, *Methanosarcina acetivorans*; Mi, *Micromonas* sp.; Mt, *M. tuberculosis*; Np, *Nostoc punctiforme*; Os, *Oryza sativa*; Pc, *Picea sitchensis*; Pf, *Plasmodium falciparum*; *Pfu*, *Pyrococcus furiosus*; Pp, *Physcomitrella patens*; Pt, *Populus trichocarpa*; Sc, *S. cerevisiae*; Si, *Setaria italica*; Sl, *S. lycopersicum*; Sp, *S. pombe*; *Spns*, *Streptococcus pneumonia*; Sy, *Synechococcus*; *Syc*, *Synechocystis*; Ta, *Thermosphaera aggregans*; Tc, *Trypanosoma cruzi*; Te, *Tetraselmis* sp.; Tg, *Toxoplasma gondii*; Th, Thaumarchaeote; Tk; *Thermococcus kodakarensis*; Tr, *T. reesei*; Tv, Trichomonas vaginalis; Vv, *Vitis vinifera*; Xl, *Xenopus laevis*; Zm, *Zea mays. DHDDS*, subunit of dehydrodolichyl diphosphate synthase.

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References

1. Wallrapp F. H., Pan J.-J., Ramamoorthy G., Almonacid D. E., Hillerich B. S., Seidel R., Patskovsky Y., Babbitt P. C., Almo S. C., Jacobson M. P., and Poulter C. D. (2013) Prediction of function for the polyprenyl transferase subgroup in the isoprenoid synthase superfamily. Proc. Natl. Acad. Sci. U.S.A. 110, E1196–E1202 - PMC - PubMed
1. Takahashi S., and Koyama T. (2006) Structure and function of cis-prenyl chain elongating enzymes. Chem. Rec. 6, 194–205 - PubMed
1. Rohmer M., Grosdemange-Billiard C., Seemann M., and Tritsch D. (2004) Isoprenoid biosynthesis as a novel target for antibacterial and antiparasitic drugs. Curr. Opin. Investig. Drugs 5, 154–162 - PubMed
1. Teng K.-H., and Liang P.-H. (2012) Structures, mechanisms and inhibitors of undecaprenyl diphosphate synthase: a cis-prenyltransferase for bacterial peptidoglycan biosynthesis. Bioorg. Chem. 43, 51–57 - PubMed
1. Shimizu N., Koyama T., and Ogura K. (1998) Molecular cloning, expression, and purification of undecaprenyl diphosphate synthase: no sequence similarity between E- and Z-prenyl diphosphate synthases. J. Biol. Chem. 273, 19476–19481 - PubMed

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[1] Wallrapp F. H., Pan J.-J., Ramamoorthy G., Almonacid D. E., Hillerich B. S., Seidel R., Patskovsky Y., Babbitt P. C., Almo S. C., Jacobson M. P., and Poulter C. D. (2013) Prediction of function for the polyprenyl transferase subgroup in the isoprenoid synthase superfamily. Proc. Natl. Acad. Sci. U.S.A. 110, E1196–E1202 - PMC - PubMed

[2] Wallrapp F. H., Pan J.-J., Ramamoorthy G., Almonacid D. E., Hillerich B. S., Seidel R., Patskovsky Y., Babbitt P. C., Almo S. C., Jacobson M. P., and Poulter C. D. (2013) Prediction of function for the polyprenyl transferase subgroup in the isoprenoid synthase superfamily. Proc. Natl. Acad. Sci. U.S.A. 110, E1196–E1202 - PMC - PubMed

[3] Takahashi S., and Koyama T. (2006) Structure and function of cis-prenyl chain elongating enzymes. Chem. Rec. 6, 194–205 - PubMed

[4] Takahashi S., and Koyama T. (2006) Structure and function of cis-prenyl chain elongating enzymes. Chem. Rec. 6, 194–205 - PubMed

[5] Rohmer M., Grosdemange-Billiard C., Seemann M., and Tritsch D. (2004) Isoprenoid biosynthesis as a novel target for antibacterial and antiparasitic drugs. Curr. Opin. Investig. Drugs 5, 154–162 - PubMed

[6] Rohmer M., Grosdemange-Billiard C., Seemann M., and Tritsch D. (2004) Isoprenoid biosynthesis as a novel target for antibacterial and antiparasitic drugs. Curr. Opin. Investig. Drugs 5, 154–162 - PubMed

[7] Teng K.-H., and Liang P.-H. (2012) Structures, mechanisms and inhibitors of undecaprenyl diphosphate synthase: a cis-prenyltransferase for bacterial peptidoglycan biosynthesis. Bioorg. Chem. 43, 51–57 - PubMed

[8] Teng K.-H., and Liang P.-H. (2012) Structures, mechanisms and inhibitors of undecaprenyl diphosphate synthase: a cis-prenyltransferase for bacterial peptidoglycan biosynthesis. Bioorg. Chem. 43, 51–57 - PubMed

[9] Shimizu N., Koyama T., and Ogura K. (1998) Molecular cloning, expression, and purification of undecaprenyl diphosphate synthase: no sequence similarity between E- and Z-prenyl diphosphate synthases. J. Biol. Chem. 273, 19476–19481 - PubMed

[10] Shimizu N., Koyama T., and Ogura K. (1998) Molecular cloning, expression, and purification of undecaprenyl diphosphate synthase: no sequence similarity between E- and Z-prenyl diphosphate synthases. J. Biol. Chem. 273, 19476–19481 - PubMed

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cis-Prenyltransferase: New Insights into Protein Glycosylation, Rubber Synthesis, and Human Diseases

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cis-Prenyltransferase: New Insights into Protein Glycosylation, Rubber Synthesis, and Human Diseases

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