“Head‐to‐Middle” and “Head‐to‐Tail” <i>cis</i>‐Prenyl Transferases: Structure of Isosesquilavandulyl Diphosphate Synthase

Ko, Tzu Ping; Chen, Lu; Malwal, Satish R.; Zhang, Jianan; Hu, Xiangying; Qu, Fiona; Liu, Weidong; Huang, Jian; Cheng, Yuanzhi; Chen, Chun‐Chi; Yang, Yunyun; Zhang, Yonghui; Oldfield, Eric; Guo, R.T.

doi:10.1002/anie.201710185

Cited by 27 publications

(26 citation statements)

References 20 publications

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“…8 The chemical structures of their substrates (dimethylallyl diphosphate 4 , and geranyl diphosphate 5 ) and products ( 1–3 ) are shown in Scheme 1b, and the X-ray structures of LPPS, CLDS and Mcl22 have recently been reported. 9–11 The mechanisms of action of LPPS and Mcl22 involve ionization (or at least partial charge separation if the mechanism is concerted 4 ) of a dimethylallyl diphosphate (DMAPP, 4 ) in the allylic S1 site followed by condensation with either 4 or 5 in the S2 site to form 1 or 2 , and this mechanism is quite similar to that reported 12 for undecaprenyl diphosphate synthase, UPPS. The mechanism of action of CLDS which forms cyclo -LPP ( 3 ) and not LPP is more complex since it involves an intermediate cyclization reaction, but in very recent work, Tomita et al 10 proposed an elegant mechanism involving a proton shift leading to a carbocation rearrangement, Scheme 2, based on isotope labeling, crystallography and computational docking.…”

Section: Introductionsupporting

confidence: 54%

“…Figure 3 shows a sequence alignment of CLDS together with six other ζ-fold proteins: CLDS, Mcl22, LPPS, a tomato cis -farnesyl diphosphate synthase (FPPS), E. coli undecaprenyl diphosphate synthase (UPPS), Mycobacterium tuberculosiscis -FPPS (Rv1086c), and M. tuberculosis decaprenyl diphosphate synthase (Rv2361c). Figure 4 shows structural alignments between CLDS and these 6 proteins 9–11, 22,23 and Figure 5a shows an alignment of the ligands and residues of mechanistic interest. All proteins have similar ζ-folds 3 with, on average, a 1.842 A Cα rmsd between CLDS and the six other proteins.…”

Section: Resultsmentioning

confidence: 99%

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Catalytic Role of Conserved Asparagine, Glutamine, Serine, and Tyrosine Residues in Isoprenoid Biosynthesis Enzymes

Malwal

Gao

et al. 2018

ACS Catal.

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We report the results of an investigation into the catalytic role of highly conserved amide (asparagine, glutamine) and OH-containing (serine, tyrosine) residues in several prenyltransferases. We first obtained the X-ray structure of cyclolavandulyl diphosphate synthase containing two molecules of the substrate analog dimethylallyl (S)-thiolodiphosphate (DMASPP). The two molecules have similar diphosphate group orientations to those seen in other ζ-fold (cis- head-to-tail and head-to-middle) prenyltransferases with one diphosphate moiety forming a bidentate chelate with Mg2+ in the so-called S1 site (which is typically the allylic binding site in ζ-fold proteins) while the second diphosphate binds to Mg2+ in the so-called S2 site (which is typically the homoallylic binding site in ζ-fold proteins) via a single P1O1 oxygen. The latter interaction can facilitate direct phosphate-mediated proton abstraction via P1O2, or more likely by an indirect mechanism in which P1O2 stabilizes a basic asparagine species that removes H+, which is then eliminated via an Asn-Ser shuttle. The universal occurrence of Asn-Ser pairs in ζ-fold proteins leads to the idea that the highly conserved amide (Asn, Gln) and OH-containing (Tyr) residues seen in many “head-to-head” prenyltransferases such as squalene and dehydrosqualene synthase might play similar roles, in H+ elimination. Structural, bioinformatics and mutagenesis investigations indeed indicate an important role of these residues in catalysis, with the results of density functional theory calculations showing that Asn bound to Mg2+ can act as a general (imine-like) base, while Gln, Tyr and H2O form a proton channel that is adjacent to the conventional (Asp-rich) “active site”. Taken together, our results lead to mechanisms of proton-elimination from carbocations in numerous prenyltransferases in which neutral species (Asn, Gln, Ser, Tyr, H2O) act as proton shuttles, complementing the more familiar roles of acidic groups (in Asp and Glu) that bind to Mg2+, and basic groups (primarily Arg) that bind to diphosphates, in isoprenoid biosynthesis.

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Section: Introductionsupporting

confidence: 54%

Section: Resultsmentioning

confidence: 99%

Catalytic Role of Conserved Asparagine, Glutamine, Serine, and Tyrosine Residues in Isoprenoid Biosynthesis Enzymes

Malwal

Gao

et al. 2018

ACS Catal.

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“…It catalyzes the head‐to‐middle (i.e., non–head‐to‐tail) condensation reaction of the C2–C3 double bond of the first allylic substrate (located at S2 site) and C1 in a second allylic substrate (located at S1 site), subsequently producing branched mono‐ or sesquiterpenes (Figure 6a). Some well‐known examples are 10‐carbon lavandulyl diphosphate (LPP), catalyzed by lavandulyl diphosphate synthase (LPPS) or Z,Z‐farnesyl diphosphate synthase (zFPS) 86,87 ; 10‐carbon cyclolavandulyl diphosphate (CLPP), catalyzed by cyclolavandulyl diphosphate synthase (CLPPS) 88 ; 15‐carbon isosesquilavandulyl diphosphate (ISLPP), catalyzed by isosesquilavandulyl diphosphate synthase (Mcl22) 89 ; and 20‐carbon geranyl lavandulyl diphosphate (GLPP), catalyzed by MA1831, a cis ‐prenyltransferase homologue from Methanosarcina acetivorans (Figure 6b–f). 90 …”

Section: Class 3: Head‐to‐middle Prenyl Synthasementioning

confidence: 99%

Structure, catalysis, and inhibition mechanism of prenyltransferase

Chang¹,

Cheng²,

Wang

2020

IUBMB Life

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Isoprenoids, also known as terpenes or terpenoids, represent a large family of natural products composed of five-carbon isopentenyl diphosphate or its isomer dimethylallyl diphosphate as the building blocks. Isoprenoids are structurally and functionally diverse and include dolichols, steroid hormones, carotenoids, retinoids, aromatic metabolites, the isoprenoid side-chain of ubiquinone, and isoprenoid attached signaling proteins. Productions of isoprenoids are catalyzed by a group of enzymes known as prenyltransferases, such as farnesyltransferases, geranylgeranyltransferases, terpenoid cyclase, squalene synthase, aromatic prenyltransferase, and cis-and trans-prenyltransferases. Because these enzymes are key in cellular processes and metabolic pathways, they are expected to be potential targets in new drug discovery. In this review, six distinct subsets of characterized prenyltransferases are structurally and mechanistically classified, including (1) head-to-tail prenyl synthase, (2) head-to-head prenyl synthase, (3) head-tomiddle prenyl synthase, (4) terpenoid cyclase, (5) aromatic prenyltransferase, and (6) protein prenylation. Inhibitors of those enzymes for potential therapies against several diseases are discussed. Lastly, recent results on the structures of integral membrane enzyme, undecaprenyl pyrophosphate phosphatase, are also discussed.

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“…X‐ray crystallography analyses have revealed that the protein structures of UPP synthase (UPPS), LPPS, CLDS, and Mcl22 adopt a typical fold for the cis ‐type IDS family (Figure ). These structures have allowed mechanistic and structural comparison among the cis ‐type IDS homologous enzymes.…”

Section: Coupling Mechanismmentioning

confidence: 99%

Structural and Mechanistic Insight into Terpene Synthases that Catalyze the Irregular Non‐Head‐to‐Tail Coupling of Prenyl Substrates

Kobayashi

Kuzuyama

2018

ChemBioChem

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Terpenoids have diverse structures and thus represent an important class of biologically active natural products. The structural diversity of terpenoids originates from the coupling of prenyl diphosphate substrates, such as isopentenyl diphosphate and dimethylallyl diphosphate. These isoprenyl diphosphates undergo canonical and sequential “head‐to‐tail” coupling catalyzed by terpene synthases, followed by modifications such as cyclization, hydroxylation, and glycosylation. In recent years, several terpene synthases that catalyze irregular “non‐head‐to‐tail” couplings to afford branched terpenoids have been identified. This minireview describes structural and mechanistic insights into these unusual coupling reactions that provide a new strategy for the structural diversification of natural products.

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“Head‐to‐Middle” and “Head‐to‐Tail” cis‐Prenyl Transferases: Structure of Isosesquilavandulyl Diphosphate Synthase

Cited by 27 publications

References 20 publications

Catalytic Role of Conserved Asparagine, Glutamine, Serine, and Tyrosine Residues in Isoprenoid Biosynthesis Enzymes

Catalytic Role of Conserved Asparagine, Glutamine, Serine, and Tyrosine Residues in Isoprenoid Biosynthesis Enzymes

Structure, catalysis, and inhibition mechanism of prenyltransferase

Structural and Mechanistic Insight into Terpene Synthases that Catalyze the Irregular Non‐Head‐to‐Tail Coupling of Prenyl Substrates

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