Team:UST Beijing/Cyclase
Human and Ginseng Squalene Cyclase
Figure 1. Cholesterol Biosynthetic Pathway
As shown in Figure 1, the human OSC (also namely lanosterol synthesis, LAS), catalyzes the 2,3-oxidosqualene to form lanosterol via cyclization (to yield a key intermediate: protosterol cation), rearrangement, hydrogen transfer, methyl transfer, and dehydro-condensation. Lanosterol is the first sterol to be formed in the MVP and the essential intermediate to form cholesterol. This extraordinary reaction has been described as the most complicated enzyme catalytic reaction in human biology. There are two available crystal structures of human OSC (PDB ID: 1w6k and 1w6j): one contains an inhibitor RO48−8071 (1w6j) and the other contains the lanosterol (1w6k).
Figure 2. Brief Triterpenoid Biosynthetic Pathway
As seen from Figure 2, OSC enzymes are critical to sterol synthesis not only in human being but also in high plants and fungi. There are several OSC isoforms for both sterol synthesis and triterpenoid biosynthesis in the higher plants, such as PNA, bAS, and so on. After constructing the basic cyclic triterpenoid skeletons by OSC, these skeletons can form various cyclic terpene derivatives with oxidation and glycosylation. This concerted reaction also exists in another squalene cyclase, squalene-hopene cyclase (SHC). It can be seen that the product of human cyclase is Lanosterol ,and the product of ginseng cyclase is dammarenediol-II,the difference lies in the spatial structure, the position of the hydroxyl and Carbon-carbon double bonds is different. It can be seen that the two kinds of enzymes react with the same reactants, but the products are different in spatial structures and bond positions.
Figure 3. Cyclases of Nature Collections
Figure 4. Phylogenetic Trees of Ginseng Cyclase
We put the ginseng cyclase sequence into NCBI, compareing with the sequence of similar species, saving the alignment results, into the CLC, and then the human cyclase sequence is also introduced into the CLC, and made a phylogenetic trees. From the phylogenetic trees we can see that ginseng cyclase and human cyclase are far apart. It shows that their sequence are different. Crystal structure of their primary also have a marked difference. According to Pangu algorithm and literature, we choose people cyclase 1w6k and ginseng cyclase combined, we obtain the required Pangu cyclase.
Cholesterol Physiology
Figure 5. Skeletal Formula & Accumulation on Vascular Wall
Cholesterol (CT), which is ubiquitous in human body, and it plays a significant role in biochemistry. One of the prime reasons is that CT is an essential component for biological membrane, and it is used to maintain the strength and fluidity of the cell membrane as well. And CT also is the precursor substance for bile acid , vitamin D, and sex hormone in animals cells. However, CT is poorly soluble in water, and flows in vessels as combination with high density lipoprotein (HDL) and low density lipoprotein (HDL). What if cholesterol metabolism is inhibited ? Disturbance of lipid metabolism may cause the result that CT is more than the need of cells and surplus fat deposition in the blood-vessel. Blood circulation gets worse and causes risky diseases such as Atherosclerosis, hardening of the arteries.
Cholesterol Oxidation
Squalene could be synthesized by acetyl-CoA widely existing in human body, and notoginseng.2,3-oxidosqualene is its next compound, LAS transfers oxidosqualene into dammarenediol-II in notoginseng. Under the work of free radicals, it changes structure into PNA and stimulate cholesterol metabolism. At the same time, lanosterol is produced via PNS pathway, and it’s unstable to exist so that it turns to cholesterol immediately. CT reacts to free radicals and its product will inhibit cholesterol metabolism.
Figure 6. Cholesterol Oxidation Pathway
Reference
Chen, N., Zhou, J., Li, J., Xu, J., & Wu, R. (2014). Concerted cyclization of lanosterol C-ring and D-ring under human oxidosqualene cyclase catalysis: an ab initio QM/MM MD study. Journal of chemical theory and computation, 10(3), 1109-1120.
