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Building Synthetic Sterols Computationally - Unlocking the Secrets of Evolution?

Róg T, Pöyry S, Vattulainen I - Front Bioeng Biotechnol (2015)

Bottom Line: To this end, we discuss recent atomistic molecular dynamics simulation studies that have predicted new synthetic sterols with properties comparable to those of cholesterol.We also discuss more recent experimental studies that have vindicated these predictions.The paper highlights the strength of computational simulations in making predictions for synthetic biology, thereby guiding experiments.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, Tampere University of Technology , Tampere , Finland.

ABSTRACT
Cholesterol is vital in regulating the physical properties of animal cell membranes. While it remains unclear what renders cholesterol so unique, it is known that other sterols are less capable in modulating membrane properties, and there are membrane proteins whose function is dependent on cholesterol. Practical applications of cholesterol include its use in liposomes in drug delivery and cosmetics, cholesterol-based detergents in membrane protein crystallography, its fluorescent analogs in studies of cholesterol transport in cells and tissues, etc. Clearly, in spite of their difficult synthesis, producing the synthetic analogs of cholesterol is of great commercial and scientific interest. In this article, we discuss how synthetic sterols non-existent in nature can be used to elucidate the roles of cholesterol's structural elements. To this end, we discuss recent atomistic molecular dynamics simulation studies that have predicted new synthetic sterols with properties comparable to those of cholesterol. We also discuss more recent experimental studies that have vindicated these predictions. The paper highlights the strength of computational simulations in making predictions for synthetic biology, thereby guiding experiments.

No MeSH data available.


Structures of (A) lanosterol, (B) cholesterol, and (C) Dchol. Chemical structures and atom numberings are shown on the left. The sites where differences occur between lanosterol and cholesterol have been colored with pink, and the methyl groups that are removed in Dchol are marked in yellow. In the middle and on the right, space-filling models of the same molecules are given. The middle panel shows only the ring system of each sterol. The point of view is from the direction of the hydroxyl group, and the ring system lies on the perpendicular plane. The off-plane methyl groups are colored in orange, and carbons in cyan. On the right, space-filling models of the whole sterol molecules are shown as side views, the ring system lying on the horizontal plane. The off-plane methyl groups are colored in orange, carbons in cyan, oxygen in red, and hydrogen in silver.
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Figure 1: Structures of (A) lanosterol, (B) cholesterol, and (C) Dchol. Chemical structures and atom numberings are shown on the left. The sites where differences occur between lanosterol and cholesterol have been colored with pink, and the methyl groups that are removed in Dchol are marked in yellow. In the middle and on the right, space-filling models of the same molecules are given. The middle panel shows only the ring system of each sterol. The point of view is from the direction of the hydroxyl group, and the ring system lies on the perpendicular plane. The off-plane methyl groups are colored in orange, and carbons in cyan. On the right, space-filling models of the whole sterol molecules are shown as side views, the ring system lying on the horizontal plane. The off-plane methyl groups are colored in orange, carbons in cyan, oxygen in red, and hydrogen in silver.

Mentions: The biosynthesis of cholesterol is a complex process. The first sterol on the path is lanosterol (Figure 1), which is synthesized from squalene in a reaction that requires molecular oxygen. Consequently, the occurrence of this sterol can be located in the history of earth to a time after prokaryotic life had developed. Thus, perhaps not surprisingly, sterols are not typical bacterial lipids with the exception of Mycoplasma, one of the most simple parasitic bacteria that utilizes lipids produced by their hosts and is actually often thought of as an intermediate form of life between viruses and bacteria. Next, lanosterol is converted into cholesterol through two alternative pathways: one ending in desmosterol and another with 7-dehydrocholesterol – the direct precursors of cholesterol. Although textbooks show these as separate pathways, it should be kept in mind that at each of the individual steps, it is possible to swap to the other pathway, as appropriate enzymes for this do exist. The conversion of lanosterol to cholesterol needs a minimum of only 7 steps; however, 18 steps are possible and thus also 18 enzymes exist! This has to be energetically very expensive for cells, once more stressing the great importance of cholesterol.


Building Synthetic Sterols Computationally - Unlocking the Secrets of Evolution?

Róg T, Pöyry S, Vattulainen I - Front Bioeng Biotechnol (2015)

Structures of (A) lanosterol, (B) cholesterol, and (C) Dchol. Chemical structures and atom numberings are shown on the left. The sites where differences occur between lanosterol and cholesterol have been colored with pink, and the methyl groups that are removed in Dchol are marked in yellow. In the middle and on the right, space-filling models of the same molecules are given. The middle panel shows only the ring system of each sterol. The point of view is from the direction of the hydroxyl group, and the ring system lies on the perpendicular plane. The off-plane methyl groups are colored in orange, and carbons in cyan. On the right, space-filling models of the whole sterol molecules are shown as side views, the ring system lying on the horizontal plane. The off-plane methyl groups are colored in orange, carbons in cyan, oxygen in red, and hydrogen in silver.
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Related In: Results  -  Collection

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Figure 1: Structures of (A) lanosterol, (B) cholesterol, and (C) Dchol. Chemical structures and atom numberings are shown on the left. The sites where differences occur between lanosterol and cholesterol have been colored with pink, and the methyl groups that are removed in Dchol are marked in yellow. In the middle and on the right, space-filling models of the same molecules are given. The middle panel shows only the ring system of each sterol. The point of view is from the direction of the hydroxyl group, and the ring system lies on the perpendicular plane. The off-plane methyl groups are colored in orange, and carbons in cyan. On the right, space-filling models of the whole sterol molecules are shown as side views, the ring system lying on the horizontal plane. The off-plane methyl groups are colored in orange, carbons in cyan, oxygen in red, and hydrogen in silver.
Mentions: The biosynthesis of cholesterol is a complex process. The first sterol on the path is lanosterol (Figure 1), which is synthesized from squalene in a reaction that requires molecular oxygen. Consequently, the occurrence of this sterol can be located in the history of earth to a time after prokaryotic life had developed. Thus, perhaps not surprisingly, sterols are not typical bacterial lipids with the exception of Mycoplasma, one of the most simple parasitic bacteria that utilizes lipids produced by their hosts and is actually often thought of as an intermediate form of life between viruses and bacteria. Next, lanosterol is converted into cholesterol through two alternative pathways: one ending in desmosterol and another with 7-dehydrocholesterol – the direct precursors of cholesterol. Although textbooks show these as separate pathways, it should be kept in mind that at each of the individual steps, it is possible to swap to the other pathway, as appropriate enzymes for this do exist. The conversion of lanosterol to cholesterol needs a minimum of only 7 steps; however, 18 steps are possible and thus also 18 enzymes exist! This has to be energetically very expensive for cells, once more stressing the great importance of cholesterol.

Bottom Line: To this end, we discuss recent atomistic molecular dynamics simulation studies that have predicted new synthetic sterols with properties comparable to those of cholesterol.We also discuss more recent experimental studies that have vindicated these predictions.The paper highlights the strength of computational simulations in making predictions for synthetic biology, thereby guiding experiments.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, Tampere University of Technology , Tampere , Finland.

ABSTRACT
Cholesterol is vital in regulating the physical properties of animal cell membranes. While it remains unclear what renders cholesterol so unique, it is known that other sterols are less capable in modulating membrane properties, and there are membrane proteins whose function is dependent on cholesterol. Practical applications of cholesterol include its use in liposomes in drug delivery and cosmetics, cholesterol-based detergents in membrane protein crystallography, its fluorescent analogs in studies of cholesterol transport in cells and tissues, etc. Clearly, in spite of their difficult synthesis, producing the synthetic analogs of cholesterol is of great commercial and scientific interest. In this article, we discuss how synthetic sterols non-existent in nature can be used to elucidate the roles of cholesterol's structural elements. To this end, we discuss recent atomistic molecular dynamics simulation studies that have predicted new synthetic sterols with properties comparable to those of cholesterol. We also discuss more recent experimental studies that have vindicated these predictions. The paper highlights the strength of computational simulations in making predictions for synthetic biology, thereby guiding experiments.

No MeSH data available.