Lovastatin-synthesizing enzyme successfully reconstituted...

Lovastatin is a member of the drug class of statins, used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. Lovastatin is a naturally occurring drug found in food such as oyster mushrooms and red yeast rice. When I was working with a Banglore based company (Biocon), they did try this compound and I think the company is marketing this drug now. As for as my knowledge goes there were two ways to synthesise 'biosynthesis using Dield-Alder catalyzed cyclization' & 'biosyntheis using broadly specific acyltransferase'

Dield-Alder catalysed cyclisation : In vitro formation of a triketide lactone using a genetically-modified protein derived from 6-deoxyerythronolide B synthase has been demonstrated. The stereochemistry of the molecule supports the intriguing idea that an enzyme-catalyzed Diels-Alder reaction may occur during assembly of the polyketide chain. It thus appears that biological Diels-Alder reactions may be triggered by generation of reactive triene systems on an enzyme surface.

Biosynthesis using broadly specific acyltransferase : It has been found that a dedicated acyltransferase, LovD, is encoded in the lovastatin biosynthetic pathway. LovD has a broad substrate specificity towards the acyl carrier, the acyl substrate and the decalin acyl acceptor. It efficiently catalyzes the acyl transfer from coenzyme A thoesters or N-acetylcysteamine (SNAC) thioesters to monacolin J. The biosynthesis of lovastatin is coordinated by two iterative type I polyketide syntheses and numerous accessory enzymes. Nonketide, the intermediate biosynthetic precursor of lovastatin, is assembled by the upstream megasynthase LovB (also known as lovastatin nonaketide synthase), enoylreductase LovC, and CYP450 oxygenases.

Recently more interesting out come from a group of UCLA researchers is that, for the first time thy have successfully reconstituted in the laboratory the enzyme responsible for producing the blockbuster cholesterol-lowering drug lovastatin. As per the claim by the researchers, the lovastatin-synthesizing enzyme is one of the most interesting but least understood of the polyketide synthases, which are found in filamentous fungi and which play a crucial role in the synthesis of "small molecule natural products" — pharmacologically or biologically potent compounds produced by living organisms, many of which are the active ingredients in pharmaceuticals.

This finding is of great significance because commonly used antibiotics, such as tetracycline, are produced by polyketide synthases. Polyketides represent a class of 7,000 known structures, of which more than 20 are commercial drugs, including the immunosuppressant rapamycin, the antibiotic erythromycin and the anticancer drug doxorubicin. In their study studied the enzyme that makes a small-molecule precursor to lovastatin. The real difference about this enzyme, is its extraoridnarily large size in comparison to all other enzymes so for studied. As per the claim by the lead researcher Dr. Yi Tang, "It's one of the largest enzymes ever to be reconstituted in a test tube. It is 10 times the size of most enzymes people study & the enzyme has seven active sites and catalyzes more than 40 different reactions that eventually result in an important precursor to lovastatin. Hope with this remarkable achievement, one can prepare many natural products in the lab in the days to come.

Ref : http://www.newsroom.ucla.edu/portal/ucla/ucla-engineering-researchers-have-111812.aspx

Lovastatin: A New Weapon Against Plague?

We know that, Lovastatin is a member of the drug class of statins,  used for lowering  cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. Lovastatin is a naturally occurring drug found in food such as oyster mushrooms  and red yeast rice.

Now scientists at the Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (CNRS/Université Aix-Marseille 2), have found that Lovastatin protects animals against the deadly effects of plague.

After inoculating small rodents with the Yersinia pestis bacterium, the team led by Didier Raoult and Michel Drancourt at the URMITE (CNRS/Université Aix-Marseille 2) showed that animals treated with lovastatin presented fewer and less severe infections. Lovastatin therefore has preventive properties against plague mortality in an animal model. This experimental study also reveals that this statin has no direct antibiotic effect against Yersinia pestis but that it prevents the development of septicemia.  

Researchers conclude that Lovastatin had no in-vitro antibiotic effect against Y. pestis. The difference in the mortality between control mice (11/15; 73.5%) and lovastatin-treated mice (3/15; 20%) was significant (P<0.004; Mantel-Haenszel test). Dead mice exhibited Y. pestis septicemia and inflammatory destruction of lung and spleen tissues not seen in lovastatin-treated surviving mice. These data suggest that lovastatin may help prevent the deadly effects of plague, with a caution that field observations are warranted to assess the role of lovastatin in the prophylaxis of human plague....

Ref : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0010928

Lovastatin for the treatment of degenerative disc disease ?

We know that Lovastatin is a member of the drug class of statins, used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. But recentlyDr. Yang and his research group has come up with new innovative idea that Lovastatin, helps the differentiation of disc cells in vitro.

Degenerative disc disease is one of the leading sources of back and neck pain. Disc degeneration is part of the normal aging of the spine. In this condition, the spinal discs (the pillow-like pads between the bones) lose their cushioning. When this happens, it can cause persistent pain in the lower back, legs, neck or arms. Treatments for pain can include medications and physical therapy. Sometimes surgery is needed if the pain is severe and keeps a person from participating in everyday activities.

In their quest to discover ways to stop or reverse degenerative disc disease, orthopaedic researchers have been removing disc tissue from patients who are having spine surgery and extracting cells from that tissue for cultivation in vitro (a controlled environment outside of a living organism). They then transfer the cells back into the patient. Shu-Hua Yang, MD, PhD, is part of a Taiwanese research team that has discovered that Lovastatin, a cholesterol-lowering medication, helps the differentiation of disc cells in vitro.

The results are of great interest : 1. the number of nucleus pulposus cells had increased; 2. Lovastatin increased the synthesis of collagen II, a protein that makes up moveable joints, and decreased the synthesis of collagen I, a protein that is related to fibrosis and 3. Lovastatin had no cytotoxicity (the quality of being toxic) on nucleus pulposus cells..

I think if proven, one more addition to the list of serendipity.......

Though further studeis are essential to establish their claim, its a good beginning..

Common cholesterol-lowering drug may help protect against cerebral malaria

In continuation of my update lovastatin

Researchers have discovered that adding lovastatin, a widely used cholesterol-lowering drug, to traditional antimalarial treatment decreases neuroinflammation and protects against cognitive impairment in a mouse model of cerebral malaria. Although there are differences between mouse models of cerebral malaria and human disease, these new findings indicate that statins are worthy of consideration in clinical trials of cerebral malaria. 

Statins, a class of drugs best known for their ability to lower cholesterol, have also been shown to be active in modulating a variety of immune system responses. In their research, Zimmerman and his Brazilian colleagues evaluated the effect of statins in a mouse model of cerebral malaria. The researchers found that adding a drug called lovastatin to traditional antimalarial therapy prevented cognitive dysfunction in mice infected with cerebral malaria. They discovered that addition of lovastatin decreased white blood cell accumulation and leakiness in blood vessels in the brain. Lovastatin also reduced production of damaging oxygen-containing molecules and other factors that promote inflammation.

"The molecular mechanisms that give rise to cerebral malaria and subsequent cognitive dysfunction are not yet known," says Zimmerman. "However, the fact that statin treatment decreases both injurious blood vessel inflammation and cognitive dysfunction suggests that a combination of vascular and inflammatory triggers leads to cerebral pathology and intellectual deficits."

Ref : http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1003099

Common cholesterol-lowering drug may help protect against cerebral malaria

Statins Help the Heart, No Matter What Your Age

Cholesterol-lowering statins are already known to help cut heart risks for seniors and the middle-aged. Now, research confirms the meds can also help people aged 75 and older.

"Statin therapy has been shown to prevent cardiovascular disease in a wide range of people, but there has been uncertainty about its efficacy and safety among older people," said lead investigator Anthony Keech. He's a professor of medicine, cardiology and epidemiology at the University of Sydney in Australia.

He and colleagues at the University of Oxford in England analyzed the findings of 28 large clinical trials of statins. The trials involved nearly 187,000 people in six age groups: younger than 55; 55 to 60; 60 to 65; 65 to 70; 70 to 75; and older than 75.

"Our study summarized all the available evidence from major trials to help clarify this issue. We found that there were significant reductions in major vascular events in each of the six age groups considered, including patients [who were] aged over 75 at the start of treatment," Keech said in an Oxford news release.

Major vascular events included heart attack, stroke and procedures to clear clogged arteries.

"Statin therapy appears to be just as effective in people aged over 75 years as it is in younger people," study co-investigator Jordan Fulcher said in the news release. Fulcher is a cardiovascular research fellow at the University of Sydney.

"We have definitive evidence that statins benefit older people who have suffered a heart attack or stroke. Fewer healthy older people were represented in these trials, so more information in this group of people would help confirm the same benefits that we see in our overall trials population," he said.

Fulcher noted that a new randomized trial in Australia is exploring whether statins prolong disability-free survival in a healthy population.

The risk of heart attacks and strokes rises sharply with age, yet statins are not used as widely in older people as they should be, study co-investigator Colin Baigent said in the news release. He's director of Oxford's Medical Research Council Population Health Research Unit.

"Since the risk of heart attack and stroke increases with age, the potential benefits are likely to be even greater for older people," he said.

"Therefore, there is a need to ensure that patients at risk of cardiovascular disease due to their age are offered statin therapy where there is good reason to believe that it will be beneficial," Baigent said.

Anyone with concerns about whether statin therapy is right for them should discuss it with their health care provider, he added.

Statin use alone or with metformin may increase survival in high-risk prostate cancer patients

In continuation of my update on metformin

Among high-risk prostate cancer patients - those with high PSA and Gleason scores of 8 or more - many will develop a difficult-to-treat disease. Preliminary research suggests that two commonly prescribed medications, cholesterol-lowering statins and the diabetes therapy metformin may have anticancer effects. However, it is unclear which of these two medications - commonly prescribed together -- contributes the most and whether they can impact high-risk prostate cancer. New research shows that statins, alone or with metformin, increase survival in men with high-risk prostate cancer.

"Both metformin and statins have been associated with longer life in prostate cancer patients, yet because they are commonly prescribed together, no study we know of has looked at these two medications separately," says senior author Grace Lu-Yao, PhD, associate director of Population Science at the Sidney Kimmel Cancer Center--Jefferson Health, one of only eight NCI-designated cancer centers nationwide with a prostate cancer program of excellence.

The study, published in Cancer Medicine on Feb 8th, looked at a number of statin therapies, and metformin, an anti-diabetic medication, in high-risk prostate cancer populations.

Using data from the Surveillance, Epidemiology and End Results (SEER-18) database linked with Medicare files, Dr. Lu-Yao and colleagues looked at patients diagnosed with cancer from 2007 through to 2011. Based on 12,700 patients, the researchers observed that statins alone or in combination with metformin was significantly associated with reduced mortality from all causes.

Dr. Lu-Yao and colleagues saw the highest median survival of 3.9 months in men who took both metformin and statins, 3.6 with statins alone and 3.1 years with metformin alone. The median survival for those who did not use either drug was also 3.1 years.

With respect to prostate mortality, metformin plus statin was associated with a 36% reduction in risk of death followed by statins alone. Those taking metformin alone were relatively rare, and there was no significant association with all-cause mortality."

Interestingly, the study revealed that men who took atorvastatin, pravastatin, or rosuvastatin - but not lovastatin - demonstrated a reduction in mortality compared with non-users, which is consistent with the findings from a recent population-based cohort study using Taiwan National Health Insurance Research Data. The Taiwanese research showed that these three statins are more effective at lowering triglycerides and low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol than other statins in patients with hypercholesterolemia.

Of the three statins studied, men on atorvastatin did have a longer median time to progression on androgen deprivation therapy compared to those who weren't treated with statins. "Although the exact mechanisms remain unknown, it is worth noting that atorvastatin exhibits a potent lipid-lowering effect per dose of any statin, and has the greatest bioavailability and one of the longest half-lives," says to Dr. Lu-Yao.

The data presented in the current study provide crucial insight for the design of future randomized clinical trials of statin for high-risk patients with prostate cancer. Based on the existing evidence, a well-designed clinical trial is warranted to investigate the roles of statins and combination statins/metformin to reduce the mortality cancer of the prostate.

"Our study showed that the effects were more pronounced in patients taking statins after the diagnosis of prostate cancer, 54% reduction in PCA mortality among patients with high-risk prostate cancer," says Lu-Yao. "This magnitude of reduction is comparable to the results of men treated with androgen signaling inhibitors." Statins are relatively inexpensive with good safety records. Further studies to understand the mechanisms of the observed association and its potential clinical utility are warranted.

https://onlinelibrary.wiley.com/doi/full/10.1002/cam4.2862