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PDBsum entry 1sqc
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Contents |
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* Residue conservation analysis
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Enzyme class 2:
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E.C.4.2.1.129
- squalene--hopanol cyclase.
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Reaction:
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squalene + H2O = hopan-22-ol
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squalene
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+
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H2O
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=
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hopan-22-ol
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Enzyme class 3:
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E.C.5.4.99.17
- squalene--hopene cyclase.
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Pathway:
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Reaction:
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squalene = hop-2229-ene
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squalene
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=
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hop-22(29)-ene
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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Science
277:1811-1815
(1997)
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PubMed id:
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Structure and function of a squalene cyclase.
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K.U.Wendt,
K.Poralla,
G.E.Schulz.
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ABSTRACT
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The crystal structure of squalene-hopene cyclase from Alicyclobacillus
acidocaldarius was determined at 2.9 angstrom resolution. The mechanism and
sequence of this cyclase are closely related to those of 2,3-oxidosqualene
cyclases that catalyze the cyclization step in cholesterol biosynthesis. The
structure reveals a membrane protein with membrane-binding characteristics
similar to those of prostaglandin-H2 synthase, the only other reported protein
of this type. The active site of the enzyme is located in a large central cavity
that is of suitable size to bind squalene in its required conformation and that
is lined by aromatic residues. The structure supports a mechanism in which the
acid starting the reaction by protonating a carbon-carbon double bond is an
aspartate that is coupled to a histidine. Numerous surface alpha helices are
connected by characteristic QW-motifs (Q is glutamine and W is tryptophan) that
tighten the protein structure, possibly for absorbing the reaction energy
without structural damage.
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Selected figure(s)
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Figure 1.
Fig. 1. The proposed reaction steps in squalene-hopene
cyclases involving carbocationic intermediates. The general acid
B[1]:H protonates (H) squalene at C3, whereas the general base
B[2] deprotonates at C29 of the hopenyl cation. In a side
reaction, the cation is hydroxylated^ forming hopan-22-ol.
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Figure 5.
Fig. 5. The color-coded surface representations (30) with
nonpolar (yellow), positive (blue), and negative (red) areas.
(A) View similar to Fig. 2 but rotated around a vertical axis
and^ sliced. The cutting plane (checked) opens the large
internal cavity with the bound inhibitor LDAO. The nonpolar
channel runs to the^ left, opening into a nonpolar plateau. The
channel constriction (C) appears closed, but it is mobile enough
to be readily opened. At the upper left, hopane (two views) is
shown at scale. (B) View similar to Fig. 2 directly onto the
1600 Å2 nonpolar plateau with the channel entrance (E) at
its center and two nonpolar side chains pointing to the outside.
This is the only large nonpolar region on the surface.
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The above figures are
reprinted
by permission from the AAAs:
Science
(1997,
277,
1811-1815)
copyright 1997.
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Figures were
selected
by the author.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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G.E.Schulz
(2011).
A new classification of membrane protein crystals.
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J Mol Biol,
407,
640-646.
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M.Köksal,
Y.Jin,
R.M.Coates,
R.Croteau,
and
D.W.Christianson
(2011).
Taxadiene synthase structure and evolution of modular architecture in terpene biosynthesis.
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Nature,
469,
116-120.
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PDB codes:
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P.D.Kiser,
and
K.Palczewski
(2010).
Membrane-binding and enzymatic properties of RPE65.
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Prog Retin Eye Res,
29,
428-442.
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R.Cao,
Y.Zhang,
F.M.Mann,
C.Huang,
D.Mukkamala,
M.P.Hudock,
M.E.Mead,
S.Prisic,
K.Wang,
F.Y.Lin,
T.K.Chang,
R.J.Peters,
and
E.Oldfield
(2010).
Diterpene cyclases and the nature of the isoprene fold.
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Proteins,
78,
2417-2432.
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R.R.Knowles,
and
E.N.Jacobsen
(2010).
Attractive noncovalent interactions in asymmetric catalysis: links between enzymes and small molecule catalysts.
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Proc Natl Acad Sci U S A,
107,
20678-20685.
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R.R.Knowles,
S.Lin,
and
E.N.Jacobsen
(2010).
Enantioselective thiourea-catalyzed cationic polycyclizations.
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J Am Chem Soc,
132,
5030-5032.
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G.P.Ghimire,
T.J.Oh,
H.C.Lee,
and
J.K.Sohng
(2009).
Squalene-hopene cyclase (Spterp25) from Streptomyces peucetius: sequence analysis, expression and functional characterization.
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Biotechnol Lett,
31,
565-569.
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K.Y.Wong,
J.P.Richard,
and
J.Gao
(2009).
Theoretical analysis of kinetic isotope effects on proton transfer reactions between substituted alpha-methoxystyrenes and substituted acetic acids.
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J Am Chem Soc,
131,
13963-13971.
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L.K.Ranzer,
T.B.Brück,
W.M.Brück,
J.V.Lopez,
and
R.G.Kerr
(2009).
A new prokaryotic farnesyldiphosphate synthase from the octocoral eunicea fusca: differential display, inverse PCR, cloning, and characterization.
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Mar Biotechnol (NY),
11,
62-73.
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T.Frickey,
and
E.Kannenberg
(2009).
Phylogenetic analysis of the triterpene cyclase protein family in prokaryotes and eukaryotes suggests bidirectional lateral gene transfer.
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Environ Microbiol,
11,
1224-1241.
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Y.Wang,
R.I.Sadreyev,
and
N.V.Grishin
(2009).
PROCAIN: protein profile comparison with assisting information.
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Nucleic Acids Res,
37,
3522-3530.
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D.W.Christianson
(2008).
Unearthing the roots of the terpenome.
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Curr Opin Chem Biol,
12,
141-150.
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J.D.King,
E.F.Mulrooney,
E.Vinogradov,
B.Kneidinger,
K.Mead,
and
J.S.Lam
(2008).
lfnA from Pseudomonas aeruginosa O12 and wbuX from Escherichia coli O145 encode membrane-associated proteins and are required for expression of 2,6-dideoxy-2-acetamidino-L-galactose in lipopolysaccharide O antigen.
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J Bacteriol,
190,
1671-1679.
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J.L.Kirschvink,
and
R.E.Kopp
(2008).
Palaeoproterozoic ice houses and the evolution of oxygen-mediating enzymes: the case for a late origin of photosystem II.
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Philos Trans R Soc Lond B Biol Sci,
363,
2755-2765.
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R.P.McAndrew,
Y.Wang,
A.W.Mohsen,
M.He,
J.Vockley,
and
J.J.Kim
(2008).
Structural basis for substrate fatty acyl chain specificity: crystal structure of human very-long-chain acyl-CoA dehydrogenase.
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J Biol Chem,
283,
9435-9443.
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PDB code:
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T.Bosak,
R.M.Losick,
and
A.Pearson
(2008).
A polycyclic terpenoid that alleviates oxidative stress.
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Proc Natl Acad Sci U S A,
105,
6725-6729.
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A.Pearson,
S.R.Flood Page,
T.L.Jorgenson,
W.W.Fischer,
and
M.B.Higgins
(2007).
Novel hopanoid cyclases from the environment.
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Environ Microbiol,
9,
2175-2188.
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F.S.Mathews,
M.M.Gordon,
Z.Chen,
K.R.Rajashankar,
S.E.Ealick,
D.H.Alpers,
and
N.Sukumar
(2007).
Crystal structure of human intrinsic factor: cobalamin complex at 2.6-A resolution.
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Proc Natl Acad Sci U S A,
104,
17311-17316.
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PDB code:
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I.Abe
(2007).
Enzymatic synthesis of cyclic triterpenes.
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Nat Prod Rep,
24,
1311-1331.
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R.Rasteiro,
and
J.B.Pereira-Leal
(2007).
Multiple domain insertions and losses in the evolution of the Rab prenylation complex.
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BMC Evol Biol,
7,
140.
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S.Prisic,
J.Xu,
R.M.Coates,
and
R.J.Peters
(2007).
Probing the role of the DXDD motif in Class II diterpene cyclases.
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Chembiochem,
8,
869-874.
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C.Dürr,
H.J.Schnell,
A.Luzhetskyy,
R.Murillo,
M.Weber,
K.Welzel,
A.Vente,
and
A.Bechthold
(2006).
Biosynthesis of the terpene phenalinolactone in Streptomyces sp. Tü6071: analysis of the gene cluster and generation of derivatives.
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Chem Biol,
13,
365-377.
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H.R.Corradi,
A.V.Corrigall,
E.Boix,
C.G.Mohan,
E.D.Sturrock,
P.N.Meissner,
and
K.R.Acharya
(2006).
Crystal structure of protoporphyrinogen oxidase from Myxococcus xanthus and its complex with the inhibitor acifluorfen.
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J Biol Chem,
281,
38625-38633.
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PDB codes:
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J.Wuerges,
G.Garau,
S.Geremia,
S.N.Fedosov,
T.E.Petersen,
and
L.Randaccio
(2006).
Structural basis for mammalian vitamin B12 transport by transcobalamin.
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Proc Natl Acad Sci U S A,
103,
4386-4391.
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PDB codes:
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P.W.Fowler,
and
P.V.Coveney
(2006).
A computational protocol for the integration of the monotopic protein prostaglandin H2 synthase into a phospholipid bilayer.
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Biophys J,
91,
401-410.
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R.E.Summons,
A.S.Bradley,
L.L.Jahnke,
and
J.R.Waldbauer
(2006).
Steroids, triterpenoids and molecular oxygen.
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Philos Trans R Soc Lond B Biol Sci,
361,
951-968.
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S.P.Matsuda,
W.K.Wilson,
and
Q.Xiong
(2006).
Mechanistic insights into triterpene synthesis from quantum mechanical calculations. Detection of systematic errors in B3LYP cyclization energies.
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Org Biomol Chem,
4,
530-543.
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K.U.Wendt
(2005).
Enzyme mechanisms for triterpene cyclization: new pieces of the puzzle.
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Angew Chem Int Ed Engl,
44,
3966-3971.
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L.A.Wessjohann,
E.Ruijter,
D.Garcia-Rivera,
and
W.Brandt
(2005).
What can a chemist learn from nature's macrocycles?--a brief, conceptual view.
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Mol Divers,
9,
171-186.
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M.Ceruti,
G.Balliano,
F.Rocco,
A.Lenhart,
G.E.Schulz,
F.Castelli,
and
P.Milla
(2005).
Synthesis and biological activity of new iodoacetamide derivatives on mutants of squalene-hopene cyclase.
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Lipids,
40,
729-735.
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M.K.McKinney,
and
B.F.Cravatt
(2005).
Structure and function of fatty acid amide hydrolase.
|
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Annu Rev Biochem,
74,
411-432.
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R.A.Yoder,
and
J.N.Johnston
(2005).
A case study in biomimetic total synthesis: polyolefin carbocyclizations to terpenes and steroids.
|
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Chem Rev,
105,
4730-4756.
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S.Oliaro-Bosso,
T.Schulz-Gasch,
G.Balliano,
and
F.Viola
(2005).
Access of the substrate to the active site of yeast oxidosqualene cyclase: an inhibition and site-directed mutagenesis approach.
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Chembiochem,
6,
2221-2228.
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T.Abe,
and
T.Hoshino
(2005).
Enzymatic cyclizations of squalene analogs with threo- and erythro-diols at the 6,7- or 10,11-positions by recombinant squalene cyclase. Trapping of carbocation intermediates and mechanistic insights into the product and substrate specificities.
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Org Biomol Chem,
3,
3127-3139.
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A.Goeke,
D.Mertl,
and
G.Brunner
(2004).
A novel approach to prezizaane sesquiterpenes.
|
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Chem Biodivers,
1,
1949-1956.
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D.J.Reinert,
G.Balliano,
and
G.E.Schulz
(2004).
Conversion of squalene to the pentacarbocyclic hopene.
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Chem Biol,
11,
121-126.
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PDB code:
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E.M.Cho,
A.Okada,
H.Kenmoku,
K.Otomo,
T.Toyomasu,
W.Mitsuhashi,
T.Sassa,
A.Yajima,
G.Yabuta,
K.Mori,
H.Oikawa,
H.Toshima,
N.Shibuya,
H.Nojiri,
T.Omori,
M.Nishiyama,
and
H.Yamane
(2004).
Molecular cloning and characterization of a cDNA encoding ent-cassa-12,15-diene synthase, a putative diterpenoid phytoalexin biosynthetic enzyme, from suspension-cultured rice cells treated with a chitin elicitor.
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Plant J,
37,
1-8.
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G.Cravotto,
G.Balliano,
S.Tagliapietra,
S.Oliaro-Bosso,
and
G.M.Nano
(2004).
Novel squalene-hopene cyclase inhibitors derived from hydroxycoumarins and hydroxyacetophenones.
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Chem Pharm Bull (Tokyo),
52,
1171-1174.
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H.Luo,
A.E.Yousef,
and
H.H.Wang
(2004).
A real-time polymerase chain reaction-based method for rapid and specific detection of spoilage Alicyclobacillus spp. in apple juice.
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Lett Appl Microbiol,
39,
376-382.
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K.Poralla
(2004).
Profound insights into squalene cyclization.
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Chem Biol,
11,
12-14.
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N.V.Chandrasekharan,
and
D.L.Simmons
(2004).
The cyclooxygenases.
|
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Genome Biol,
5,
241.
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P.Benveniste
(2004).
Biosynthesis and accumulation of sterols.
|
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Annu Rev Plant Biol,
55,
429-457.
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R.Thoma,
T.Schulz-Gasch,
B.D'Arcy,
J.Benz,
J.Aebi,
H.Dehmlow,
M.Hennig,
M.Stihle,
and
A.Ruf
(2004).
Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase.
|
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Nature,
432,
118-122.
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PDB codes:
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S.Lodeiro,
M.J.Segura,
M.Stahl,
T.Schulz-Gasch,
and
S.P.Matsuda
(2004).
Oxidosqualene cyclase second-sphere residues profoundly influence the product profile.
|
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Chembiochem,
5,
1581-1585.
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S.Oliaro-Bosso,
F.Viola,
S.Matsuda,
G.Cravotto,
S.Tagliapietra,
and
G.Balliano
(2004).
Umbelliferone aminoalkyl derivatives as inhibitors of oxidosqualene cyclases from Saccharomyces cerevisiae, Trypanosoma cruzi, and Pneumocystis carinii.
|
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Lipids,
39,
1007-1012.
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T.Hoshino,
K.Shimizu,
and
T.Sato
(2004).
Deletion of the Gly600 residue of Alicyclobacillus acidocaldarius squalene cyclase alters the substrate specificity into that of the eukaryotic-type cyclase specific to (3S)-2,3-oxidosqualene.
|
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Angew Chem Int Ed Engl,
43,
6700-6703.
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T.Sato,
M.Kouda,
and
T.Hoshino
(2004).
Site-directed mutagenesis experiments on the putative deprotonation site of squalene-hopene cyclase from Alicyclobacillus acidocaldarius.
|
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Biosci Biotechnol Biochem,
68,
728-738.
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D.A.Berthold,
and
P.Stenmark
(2003).
Membrane-bound diiron carboxylate proteins.
|
| |
Annu Rev Plant Biol,
54,
497-517.
|
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F.Rocco,
S.O.Bosso,
F.Viola,
P.Milla,
G.Roma,
G.Grossi,
and
M.Ceruti
(2003).
Conjugated methyl sulfide and phenyl sulfide derivatives of oxidosqualene as inhibitors of oxidosqualene and squalene-hopene cyclases.
|
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Lipids,
38,
201-207.
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J.Wallace,
F.Harris,
and
D.A.Phoenix
(2003).
A statistical investigation of amphiphilic properties of C-terminally anchored peptidases.
|
| |
Eur Biophys J,
32,
589-598.
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S.Maurer-Stroh,
S.Washietl,
and
F.Eisenhaber
(2003).
Protein prenyltransferases.
|
| |
Genome Biol,
4,
212.
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D.A.Whittington,
M.L.Wise,
M.Urbansky,
R.M.Coates,
R.B.Croteau,
and
D.W.Christianson
(2002).
Bornyl diphosphate synthase: structure and strategy for carbocation manipulation by a terpenoid cyclase.
|
| |
Proc Natl Acad Sci U S A,
99,
15375-15380.
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PDB codes:
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H.Ishibashi,
K.Ishihara,
and
H.Yamamoto
(2002).
Chiral proton donor reagents: tin tetrachloride--coordinated optically active binaphthol derivatives.
|
| |
Chem Rec,
2,
177-188.
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J.Binet,
D.Thomas,
A.Benmbarek,
F.D.de,
and
P.Renaut
(2002).
Structure activity relationships of new inhibitors of mammalian 2,3-oxidosqualene cyclase designed from isoquinoline derivatives.
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| |
Chem Pharm Bull (Tokyo),
50,
316-329.
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P.H.Liang,
T.P.Ko,
and
A.H.Wang
(2002).
Structure, mechanism and function of prenyltransferases.
|
| |
Eur J Biochem,
269,
3339-3354.
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P.Milla,
A.Lenhart,
G.Grosa,
F.Viola,
W.A.Weihofen,
G.E.Schulz,
and
G.Balliano
(2002).
Thiol-modifying inhibitors for understanding squalene cyclase function.
|
| |
Eur J Biochem,
269,
2108-2116.
|
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P.Milla,
F.Viola,
S.Oliaro Bosso,
F.Rocco,
L.Cattel,
B.M.Joubert,
R.J.LeClair,
S.P.Matsuda,
and
G.Balliano
(2002).
Subcellular localization of oxidosqualene cyclases from Arabidopsis thaliana, Trypanosoma cruzi, and Pneumocystis carinii expressed in yeast.
|
| |
Lipids,
37,
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