SRD5A3 Is Required for Converting Polyprenol to Dolichol and Is Mutated in a Congenital Glycosylation Disorder

Cantagrel, Vincent; Lefeber, Dirk; Ng, Bobby G.; Guan, Ziqiang; Silhavy, Jennifer L.; Bielas, Stephanie; Lehle, Ludwig; Hombauer, Hans; Adamowicz, Maciej; Świeżewska, Ewa; Brouwer, Arjan Pm de; Blümel, Peter; Sykut-Cegielska, Jolanta; Houliston, Scott; Swistun, Dominika; Ali, Bassam R.; Dobyns, William B.; Babovic‐Vuksanovic, Dusica; Bokhoven, Hans van; Wevers, Ron A.; Raetz, Christian R. H.; Freeze, Hudson H.; Morava, Éva; Al‐Gazali, Lihadh; Gleeson, Joseph G.

doi:10.1016/j.cell.2010.06.001

Cited by 269 publications

(312 citation statements)

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“…Their biosynthesis is catalyzed by cisprenyltransferases (CPTs), and six out of nine putative CPT-encoding genes of Arabidopsis are expressed in roots (Surmacz and Swiezewska, 2011). Eukaryotic CPT performs sequential condensations of the IPP with an all-trans-initiator to form a mixture of homologous polyprenyl diphosphates, which subsequently are converted to Dols according to tissue-specific requirements (Cantagrel et al, 2010;Jozwiak et al, 2015). Structural analysis of polyisoprenoids of various species CPTs from S. cerevisiae are Rer2 and Srt1 (P35196 and Q03175); those from Arabidopsis are AtCPT1, AtCPT2, AtCPT3, AtCPT6, AtCPT7, and AtCPT9 (O80458, F4IMI8, Q8S2T1, Q8RX73, Q56Y11, and Q570Q8).…”

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confidence: 99%

Modeling of Dolichol Mass Spectra Isotopic Envelopes as a Tool to Monitor Isoprenoid Biosynthesis

et al. 2017

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The cooperation of the mevalonate (MVA) and methylerythritol phosphate (MEP) pathways, operating in parallel in plants to generate isoprenoid precursors, has been studied extensively. Elucidation of the isoprenoid metabolic pathways is indispensable for the rational design of plant and microbial systems for the production of industrially valuable terpenoids. Here, we describe a new method, based on numerical modeling of mass spectra of metabolically labeled dolichols (Dols), designed to quantitatively follow the cooperation of MVA and MEP reprogrammed upon osmotic stress (sorbitol treatment) in Arabidopsis (Arabidopsis thaliana). The contribution of the MEP pathway increased significantly (reaching 100%) exclusively for the dominating Dols, while for long-chain Dols, the relative input of the MEP and MVA pathways remained unchanged, suggesting divergent sites of synthesis for dominating and long-chain Dols. The analysis of numerically modeled Dol mass spectra is a novel method to follow modulation of the concomitant activity of isoprenoid-generating pathways in plant cells; additionally, it suggests an exchange of isoprenoid intermediates between plastids and peroxisomes.Isopentenyl diphosphate (IPP), the building block of isoprenoids, the most numerous class of secondary metabolites, is derived in plants from two pathways operating in parallel: the cytoplasmic mevalonate (MVA) and the plastidic methylerythritol phosphate (MEP) pathways (Rohmer, 1999;Pulido et al., 2012).Analysis of over 130 isoprenoids has shown that, in angiosperms under standard growth conditions, carotenoids and chlorophyll phytyl chains on the one hand and phytosterols on the other are made nearly exclusively via a single pathway (MEP and MVA, respectively), while numerous other isoprenoids, including dolichols (Dols; Skorupinska-Tudek et al., 2008), are of mixed origin (Hemmerlin et al., 2012).The cooperation of the two pathways (often called cross talk) is considered essential for plant adaptive responses to biotic and abiotic stresses. Consequently, their relative contributions to the formation of IPP are modulated, and the expression of particular genes of the MVA and MEP pathways is frequently correlated with stress (pathogen attack, elicitation, wounding, etc.;Hemmerlin et al., 2012) or plant development (Opitz et al., 2014). Interestingly, the effect of stress on the regulation of the MEP-MVA balance has so far been analyzed only qualitatively.Several methodologies have been employed to unravel the relative contributions of the MVA and MEP pathways to isoprenoids, such as metabolic labeling with isotopically labeled precursors (stable isotopes or radioisotopes were used), followed by structural analysis of the product of interest or blockage of the pathway (chemical, with pathway-specific inhibitors, or genetic), followed by quantification of the isoprenoid intermediates and/or end products. The advantages

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Modeling of Dolichol Mass Spectra Isotopic Envelopes as a Tool to Monitor Isoprenoid Biosynthesis

et al. 2017

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“…Whereas glycosylation was not investigated during the characterization of the DHDDS cases, the SRD5A3 and TMEM15 deficiencies were accompanied by altered N-glycosylation as demonstrated by abnormal glycosylation of serum transferrin [23,25]. Clinically, it is interesting to note that the DHDDS deficiency caused by the K42E substitution yielded a form of nonsyndromic retinitis pigmentosa, while the polyprenol reductase and dolichol kinase defects led to severe multi-organ dysfunctions.…”

Section: Dolichol Kinasementioning

confidence: 99%

“…The next gene associated with decreased Dol biosynthesis is steroid 5--reductase-3 (SRD5A3, OMIM ID: 611715), which encodes the polyprenol reductase enzyme [23]. Five SRD5A3 mutations have been reported so far in patients of Arabian, Turkish and Polish background.…”

Section: Steroid 5--reductase-3mentioning

confidence: 99%

“…Despite the putative loss of polyprenol reductase activity, substantial amounts of Dol-P linked oligosaccharides were observed, thus suggesting alternate biosynthesis pathways. The patients presented with severe symptoms like mental retardation, congenital heart defects and eye anomalies, ichthyosiform dermatitis and endocrine disorders [23,24].…”

Section: Steroid 5--reductase-3mentioning

confidence: 99%

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Diseases of glycosylation beyond classical congenital disorders of glycosylation

Hennet

2012

Biochimica et Biophysica Acta (BBA) - General Subjects

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BACKGROUND: Diseases of glycosylation are rare inherited disorders, which are often referred to as congenital disorders of glycosylation (CDG). Several types of CDG have been described in the last decades, encompassing defects of nucleotide-sugar biosynthesis, nucleotide-sugar transporters, glycosyltransferases and vesicular transport. Although clinically heterogeneous, most types of CDG are associated with neurological impairments ranging from severe psychomotor retardation to moderate intellectual disabilities. CDG are mainly caused by defects of N-glycosylation, owing to the simple detection of under-glycosylated serum transferrin by isoelectric focusing. SCOPE OF REVIEW: In the last years, several disorders of O-glycosylation, glycolipid and glycosaminoglycan biosynthesis have been described, which are known by trivial names not directly associated with the family of CDG. The present review outlines 64 gene defects affecting glycan biosynthesis and modifications, thereby underlining the complexity of glycosylation pathways and pointing to unexpected phenotypes and functional redundancies in the control of glycoconjugate biosynthesis. MAJOR CONCLUSIONS: The increasing application of whole-genome sequencing techniques unravels new defects of glycosylation, which are associated to moderate forms of mental disabilities. GENERAL SIGNIFICANCE: The knowledge gathered through the investigation of CDG increases the understanding of the functions associated to protein glycosylation in humans. This article is part of a Special Issue entitled Glycoproteomics.

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“…Among these, the last step in Dol biosynthesis was the least studied until the identification of members of the steroid a-reductase family, mammalian SRD5A3 and yeast Dfg10, as key enzymes responsible for polyprenol hydrogenation (Cantagrel et al, 2010). This was achieved by elucidation of the molecular basis of a rare Mendelian disease, demonstrating that mutations in the SRD5A3 or DFG10 gene cause increased polyprenol accumulation at the expense of Dol, leading to defective protein N-glycosylation.…”

Section: Introductionmentioning

confidence: 99%

POLYPRENOL REDUCTASE2 Deficiency Is Lethal in Arabidopsis Due to Male Sterility

et al. 2015

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Dolichol is a required cofactor for protein glycosylation, the most common posttranslational modification modulating the stability and biological activity of proteins in all eukaryotic cells. We have identified and characterized two genes, PPRD1 and -2, which are orthologous to human SRD5A3 (steroid 5a reductase type 3) and encode polyprenol reductases responsible for conversion of polyprenol to dolichol in Arabidopsis thaliana. PPRD1 and -2 play dedicated roles in plant metabolism. PPRD2 is essential for plant viability; its deficiency results in aberrant development of the male gametophyte and sporophyte. Impaired protein glycosylation seems to be the major factor underlying these defects although disturbances in other cellular dolicholdependent processes could also contribute. Shortage of dolichol in PPRD2-deficient cells is partially rescued by PPRD1 overexpression or by supplementation with dolichol. The latter has been discussed as a method to compensate for deficiency in protein glycosylation. Supplementation of the human diet with dolichol-enriched plant tissues could allow new therapeutic interventions in glycosylation disorders. This identification of PPRD1 and -2 elucidates the factors mediating the key step of the dolichol cycle in plant cells which makes manipulation of dolichol content in plant tissues feasible.

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SRD5A3 Is Required for Converting Polyprenol to Dolichol and Is Mutated in a Congenital Glycosylation Disorder

Cited by 269 publications

References 66 publications

Modeling of Dolichol Mass Spectra Isotopic Envelopes as a Tool to Monitor Isoprenoid Biosynthesis

Modeling of Dolichol Mass Spectra Isotopic Envelopes as a Tool to Monitor Isoprenoid Biosynthesis

Diseases of glycosylation beyond classical congenital disorders of glycosylation

POLYPRENOL REDUCTASE2 Deficiency Is Lethal in Arabidopsis Due to Male Sterility

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