Structure of a Membrane-Embedded Prenyltransferase Homologous to UBIAD1

Huang, Hua; Levin, E.J.; Liu, Shian; Bai, Yonghong; Lockless, Steve W.; Zhou, Ming

doi:10.1371/journal.pbio.1001911

Cited by 99 publications

(147 citation statements)

References 51 publications

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“…3D, E). The second line of evidence indicating that GGpp modulates intracellular trafficking of UBIAD1 is provided by structural analyses of archaeal UbiA prenyltransferases, which revealed that isoprenyl substrates are positioned in the membrane-embedded active site between conserved aspartate-rich motifs (NDXXDXXXD and DXXXD) (10,11). A residue corresponding to N102 in Fig.…”

Section: Discussionmentioning

confidence: 99%

Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Schumacher

Jun

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.orgUbiA prenyltransferase domain-containing protein-1 (UBIAD1) belongs to the UbiA superfamily of integral membrane prenyltransferases (1). These enzymes contain 8-10 transmembrane helices and catalyze transfer of isoprenyl groups to aromatic acceptors, producing a wide range of molecules such as ubiquinones, hemes, chlorophylls, vitamin E, and vitamin K. In animals, UBIAD1 catalyzes transfer of the 20-carbon geranylgeranyl moiety from geranylgeranyl pyrophosphate (GGpp) to menadione released from plant-derived phylloquinone, thereby generating the vitamin K 2 subtype, menaquinone-4 (MK-4) (2, 3).Mutations in the UBIAD1 gene are associated with Schnyder corneal dystrophy (SCD), an autosomal dominant human eye disease characterized by progressive opacification of the cornea, owing to abnormal accumulation of cholesterol and other lipids (4,5). Systemic dyslipidemia appears to be associated with some, but not all, SCD cases (6, 7). Missense mutations that alter 20 amino acid residues in UBIAD1 have been identified in 50 SCD families (8, 9). Several of these altered amino acids reside within the active site of UBIAD1 (10, 11). A link between UBIAD1 and cholesterol metabolism was first provided by coimmunoprecipitation studies that showed an association of UBIAD1 with the cholesterol biosynthetic enzyme, HMGCoA reductase (8). More recently, we showed that UBIAD1 inhibits sterol-accelerated endoplasmic reticulum (ER)-associated degradation (ERAD) of reductase (12), one of several feedback mechanisms that converge on the enzyme to maintain cholesterol homeostasis (13).Abstract UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K 2 subtype menaquinone-4. Previously, we found that sterols trigger binding of UBIAD1 to endoplasmic reticulum (ER)-localized HMG-CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids, including GGpp. This binding inhibits sterol-accelerated degradation of reductase, which contributes to feedback regulation of the enzyme. The addition to cells of geranylgeraniol (GGOH), which can become converted to GGpp, triggers release of UBIAD1 from reductase, allowing for its maximal degradation and permitting ER-to-Golgi transport of UBIAD1. Here, we further characterize geranylgeranyl-regulated transport of UBIAD1.

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Section: Discussionmentioning

confidence: 99%

Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Schumacher

Jun

et al. 2016

Journal of Lipid Research

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“…It has been proposed that this enzyme has structural and functional similarities in its catalytic mechanism to the UbiA enzyme, a member of a class and family very similar to the MenA enzyme, which was deduced from amino acid sequence analysis. 35,36 From the ndings of these comparisons, it is shown that the active site of both enzymes are extremely similar, showing no activity in when key missense mutations are introduced to the same place. The proposed mechanism of action by Huang et al 36 shows a magnesium coordinated catalyst reaction where two magnesium atoms in the active site pocket are coordinated on either wall by amino acids D198 and D202 on the right, and D106 and N102 on the le.…”

Section: Mena: 14-dihydroxy-2-naphthoate Prenyltransferasementioning

confidence: 99%

“…35,36 From the ndings of these comparisons, it is shown that the active site of both enzymes are extremely similar, showing no activity in when key missense mutations are introduced to the same place. The proposed mechanism of action by Huang et al 36 shows a magnesium coordinated catalyst reaction where two magnesium atoms in the active site pocket are coordinated on either wall by amino acids D198 and D202 on the right, and D106 and N102 on the le. A highly conserved tyrosine motif around the active site entrance (Y139) is important in coordination of substrates towards this active site to allow the reaction to occur.…”

Section: Mena: 14-dihydroxy-2-naphthoate Prenyltransferasementioning

confidence: 99%

Menaquinone biosynthesis inhibition: a review of advancements toward a new antibiotic mechanism

et al. 2018

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“…3D) and a UBIAD1 homolog from Archeoglobus fulgidus ( Af UbiA) – have been solved by X-ray crystallography to 3.3 Å and 3.2 Å resolution respectively [58, 63]. Both structures reveal a 9 transmembrane topology with an extramembrane cap domain made of three short helical segments.…”

Section: Structural Basis Of Interfacial Lipid Modificationmentioning

confidence: 99%

Structural basis for catalysis at the membrane-water interface

Dufrisne

Petrou

Clarke

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The membrane-water interface forms a uniquely heterogeneous and geometrically constrained environment for enzymatic catalysis. Integral membrane enzymes sample three environments – the uniformly hydrophobic interior of the membrane, the aqueous extramembrane region, and the fuzzy, amphipathic interfacial region formed by the tightly packed headgroups of the components of the lipid bilayer. Depending on the nature of the substrates and the location of the site of chemical modification, catalysis may occur in each of these environments. The availability of structural information for alpha-helical enzyme families from each of these classes, as well as several beta-barrel enzymes from the bacterial outer membrane, has allowed us to review here the different ways in which each enzyme fold has adapted to the nature of the substrates, products, and the unique environment of the membrane. Our focus here is on enzymes that process lipidic substrates.

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Structure of a Membrane-Embedded Prenyltransferase Homologous to UBIAD1

Abstract: A crystal structure of a member of the UbiA family of membrane-embedded prenyltransferases reveals the architecture of the active site and suggests a possible mechanism for catalysis.

Cited by 99 publications

References 51 publications

Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Menaquinone biosynthesis inhibition: a review of advancements toward a new antibiotic mechanism

Structural basis for catalysis at the membrane-water interface

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