Lanosterol synthase

Source: Wikipedia, the free encyclopedia.
lanosterol synthase
Identifiers
ExPASy
NiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
LSS
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000160285
ENSG00000281289

ENSMUSG00000033105

UniProt

P48449

Q8BLN5

RefSeq (mRNA)

NM_001001438
NM_001145436
NM_001145437
NM_002340

NM_146006

RefSeq (protein)

NP_001001438
NP_001138908
NP_001138909
NP_002331

NP_666118

Location (UCSC)Chr 21: 46.19 – 46.23 MbChr 10: 76.37 – 76.39 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Lanosterol synthase (EC 5.4.99.7) is an oxidosqualene cyclase (OSC) enzyme that converts (S)-2,3-oxidosqualene to a protosterol cation and finally to lanosterol.[5] Lanosterol is a key four-ringed intermediate in cholesterol biosynthesis.[6][7] In humans, lanosterol synthase is encoded by the LSS gene.[8][9]

In

prokaryotes that produce it.[11]

Due to the enzyme's role in

statins.[12]

Mechanism

Full-length profile.
Figure 1: Lanosterol synthase mechanism. The discrete carbocation intermediates show the non-concerted nature of the mechanism.

Though some data on the mechanism has been obtained by the use of suicide inhibitors, mutagenesis studies, and homology modeling, it is still not fully understood how the enzyme catalyzes the formation of lanosterol.[12]

Initial epoxide protonation and ring opening

See also: protonation

Before the acquisition of the protein's

X-ray crystal structure of the enzyme, the role of D455 as a proton donor to the substrate's epoxide was confirmed, though it was found that D455 is more likely stabilized by hydrogen bonding from two cysteine residues (C456 and C533) than from the earlier suggested histidine.[12]

Ring formation cascade

Epoxide protonation activates the substrate, setting off a cascade of ring forming reactions. Four rings in total (A through D) are formed, producing the cholesterol backbone.[12] Though the idea of a concerted formation of all four rings had been entertained in the past, kinetic studies with (S)-2,3-oxidosqualene analogs showed that product formation is achieved through discrete carbocation intermediates (see Figure 1). Isolation of monocyclic and bicyclic products from lanosterol synthase mutants has further weakened the hypothesis of a concerted mechanism.[14][15] Evidence suggests that epoxide ring opening and A ring formation is concerted, though.[16]

Structure

Lanosterol synthase is a two-domain monomeric protein

hydrophobic surface (6% of the total enzyme surface area) is the ER membrane-binding region (see Figure 2).[12]

The enzyme contains five fingerprint regions containing Gln-Trp motifs, which are also present in the highly analogous bacterial enzyme squalene-hopene cyclase.[12] Residues of these fingerprint regions contain stacked sidechains which are thought to contribute to enzyme stability during the highly exergonic cyclization reactions catalyzed by the enzyme.[17]

Function

Catalysis of lanosterol formation

Lanosterol synthase catalyzes the conversion of

prokaryotes have been found to express lanosterol synthase; it has been found as a soluble protein in Methylococcus capsulatus.[11]

Catalysis of epoxylanosterol formation

Lanosterol synthase also catalyzes the cyclization of 2,3;22,23-diepoxysqualene to 24(S),25-epoxylanosterol,

substrate is greater than for the monoepoxy (S)-2,3-epoxysqualene, under partial inhibition conversion of 2,3;22,23-diepoxysqualene to 24(S),25-epoxylanosterol is favored over lanosterol synthesis.[20]
This has relevance for disease prevention and treatment.

Clinical significance

Enzyme inhibitors as cholesterol-lowering drugs

Interest has grown in lanosterol synthase inhibitors as drugs to lower blood cholesterol and treat

coenzyme Q). Thus, lanosterol synthase, which is more closely tied to cholesterol biosynthesis than HMG-CoA reductase, is an attractive drug target.[21]

Lanosterol synthase inhibitors are thought to lower

VLDL cholesterol by a dual control mechanism. Studies in which lanosterol synthase is partially inhibited have shown both a direct decrease in lanosterol formation and a decrease in HMG-CoA reductase activity. The oxysterol 24(S),25-epoxylanosterol, which is preferentially formed over lanosterol during partial lanosterol synthase inhibition, is believed to be responsible for this inhibition of HMG-CoA reductase activity.[22]

Evolution

It is believed that

eukaryotes with OSCs and complex steroid machinery were present early in earth's history.[24]

References

  1. ^ a b c ENSG00000281289 GRCh38: Ensembl release 89: ENSG00000160285, ENSG00000281289 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000033105 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. PMID 6027261
    .
  6. ^
    PMID 15951028
    .
  7. ^
    PMID 5257956
    .
  8. PMID 7639730
    .
  9. S2CID 21051816
    .
  10. ^
    PMID 14766201
    .
  11. ^
    PMID 17567593
    .
  12. ^
    S2CID 364281
    .
  13. doi:10.1021/ja963228o
    .
  14. PMID 18842050
    .
  15. PMID 10814317
    .
  16. doi:10.1021/ja963227w
    .
  17. PMID 9295270
    .
  18. PMID 6046552
    .
  19. PMID 7451488
    .
  20. PMID 1445330
    .
  21. PMID 16210564
    .
  22. PMID 3667583
    .
  23. PMID 14660793
    .
  24. PMID 10446042
    .

Further reading

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Lanosterol_synthase&oldid=1217070514"