How Lipitor® Works

 
In previous postings we learned how cholesterol is made from squalene and squalene is made from the six carbon compound mevalonate [How to Make Cholesterol] [Making Squalene].

Today we'll cover the synthesis of melavonate from three molecules of the 2-carbon compound acetate.

When acetate is involved in biosynthesis reactions it is "activated" by forming a thioester linkage to coenzyme A ("thio" means sulfur). Coenzyme A was discovered by Nobel Laureate: Fritz Lipmann.

The first step in the pathway is the joining of two molecules of acetyl CoA to make the 4-carbon compound acetoacetyl CoA. Note that this molecule is still joined to coenzyme A. In the second step, another acetyl group is transferred to acetoacetyl CoA to make the 6-carbon molecule 3-hydroxyl-3-methylglutaryl CoA (HMG CoA). HMG-CoA was Monday's Molecule.

The last step is cleavage of the thioester linkage between the 6-carbon compound and CoA releasing mevalonate.

This last step is catalyzed by an enzyme called HMG-CoA reductase. This is an oxidation-reduction reaction where the reduction of HMG-CoA is coupled to the oxidation of NADPH. This enzyme is regulated inside the cell and this controls the biosynthesis of cholesterol since mevalonate is an essential intermediate in the pathway.

Lipitor® and similar drugs control cholesterol synthesis by inhibiting the enzyme HMG-CoA reductase. If we draw the substrate in a way that shows its structure, you can see that Lipitor® and Mevacor® resemble the business end of the molecule—the part that's cleaved by the enzyme. These drugs are effective inhibitors because they bind to the active site of the enzyme.



The class of HMG-CoA reductase inhibitors is called statins. They are used to control serum cholesterol levels in the hopes of reducing the risks of coronary heart disease. There don't seem to be any serious side effects to inhibiting mevalonate production in spite of the fact that mevalonate is required for synthesis of some hormones and of the essential cofactor ubiquinone [Ubiquinone and the Proton Pump].

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Parental Guidance Suggested

 

This rating was determined based on the presence of the following words:

* dead (2x)
* sex (1x)

I wonder what kind of rating I would get if Sandwalk were rated in France? Do they have a "milquetoast" rating?

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Swift Boat Funder T. Boone Pickens Reneges On John Kerry Million Dollar Offer

 
Anyone who spoke out against the war in Viet Nam and who knew Jane Fonda would get my vote. Especially if the other choice was someone who didn't even like Jane Fonda.

Do you remember the Swift Boat campaign against John Kerry? You should. It's going to be important in the next year since we're very likely to see something similar in the next Presidential election campaign.

One of the founders of Swift Boat Veterans for Truth (sic) has just offered one million dollars if Kerry can prove that there was even one lie in the ads they placed on television. Kerry takes up the challenge but, it seems as though there's some fine print ... [ Swift Boat Funder T. Boone Pickens Reneges On John Kerry Million Dollar Offer]. Imagine that.

Pickens supports Rudy Giuliani so it's unlikely that Giuliani will be swiftboated. Hmmm, I wonder who the target will be ....

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[Hat Tip: Canadian Cynic]

I'm Going to a Lecture on Intelligent Design

 
Denyse O'Leary is teaching a course on Intelligent Design at the University of St. Michael's College, University of Toronto [Denyse O'Leary's University Course on Intelligent Design].

The outline of the course was posted on Post-Darwinist [ COURSE: By Design or by Chance? An introduction to the intelligent design controversy].

Students in the course are allowed to invite a guest for one lecture and one of my friends, who shall remain nameless for now, has urged me to come along. By all accounts the course is going well and Denyse is presenting both sides of the controversy.

Tonight's lecture is ...

Session 5. Intelligent design: What the ID proponents actually say (and don’t say) Tuesday November 20, 2007

Michael Behe, author of Edge of Evolution (2007), sees actual design where, for example, Richard Dawkins, author of The Blind Watchmaker, sees the illusion of design. Who’s right? Are they both wrong?

Guest: Kirk Durston, biophysics PhD candidate at the University of Guelph.

Kirk Durston (right) is the National Director of the New Scholars Society. According to his biography on their website,

KIRK DURSTON, B.Sc (Physics), B.Sc. (Mech. Eng.), M.A. (Philosophy), Ph.D. Candidate (Biophysics) at the University of Guelph.

Kirk Durston is the National Director of the New Scholars Society. He is currently a Ph.D. candidate in Biophysics at the University of Guelph, specializing in the application of information to biopolymers. His other interests include amateur astronomy, wilderness canoeing & camping, and landscape photography & art.

What is it about creationists that they always seem to have multiple redundant degrees? In this case he has two Bachelor's degrees. What's with that?

It's easy to find out what Kirk believes because there's a Statment of Faith on the website.

The sole basis of our beliefs is the Bible, God's infallible written Word, the 66 books of the Old and New Testaments. We believe that it was uniquely, verbally and fully inspired by the Holy Spirit, and that it was written without error (inerrant) in the original manuscripts. It is the supreme and final authority in all matters on which it speaks.We accept those large areas of doctrinal teaching on which, historically, there has been general agreement among all true Christians. Because of the specialized calling of our movement, we desire to allow for freedom of conviction on other doctrinal matters, provided that any interpretation is based upon the Bible alone, and that no such interpretation shall become an issue which hinders the ministry to which God has called us.

Jeffrey Shallit had a few things to say about Kirk Durston on Recursivity [Kirk Durston: Apologist for Genocide]. This is going to be an interesting lecture.

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Who Was Adam?

 
One of the regular contributers to the comments section of Sandwalk has suggested we read Who Was Adam? by Fazale Rana and Hugh Ross. Apparently this is a very good explanation of how evolution is compatible with the Bible.

Hugh Ross is the ruler of Reasons to Believe, an organization that promotes the integration of science and fundamentalist Christianity. Here's part of their Statement of Faith.

We believe the Bible (the 66 books of the Old and New Testaments) is the Word of God, written. As a "God-breathed" revelation, it is thus verbally inspired and completely without error (historically, scientifically, morally, and spiritually) in its original writings. While God the Holy Spirit supernaturally superintended the writing of the Bible, that writing nevertheless reflects the words and literary styles of its individual human authors. Scripture reveals the being, nature, and character of God, the nature of God's creation, and especially His will for the salvation of human beings through Jesus Christ. The Bible is therefore our supreme and final authority in all matters that it addresses.

Fazale (Fuz) Rana is a biochemist who works for Hugh Ross at Reasons to Believe.

I've seen Hugh Ross in action when he was here for a two day symposium organized by Denyse O'Leary and some of her friends. Hugh Ross is a genuine kook with nothing to say that's even remotely interesting to scientists. I don't know about Fazale Rana. Has anyone read this book?

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Gene Genie #20

 

The 20th edition of Gene Genie has just been published on Bitesize Bio [Gene Genie #20].

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Genetically Speaking All Races Are Equal

 
That's what the genetics expert, Crystal, told us in her video [Crystal Tells Us about the Human Genome] ...

Now, surprisingly enough, genetically speaking all races are equal. As a matter of fact, if you took a random sample of someone's DNA, just by looking at it you could not tell whether they were African-American, Caucasian, Asian or any other race.

I guess Crystal forgot to tell Price et al. (2007) because this is what they say in the abstract of the paper they just published in PLoS Genetics ...

European Americans are often treated as a homogeneous group, but in fact form a structured population due to historical immigration of diverse source populations. Discerning the ancestry of European Americans genotyped in association studies is important in order to prevent false positive or negative associations due to population stratification and to identify genetic variants whose contribution to disease risk differs across European ancestries. Here, we investigate empirical patterns of population structure in European Americans, analyzing 4,198 samples from four genome-wide association studies to show that components roughly corresponding to northwest European, southeast European and Ashkenazi Jewish ancestry are the main sources of European American population structure. Building on this insight, we constructed a panel of 300 validated markers that are highly informative for distinguishing these ancestries. We demonstrate that this panel of markers can be used to correct for stratification in association studies that do not generate dense genotype data.

So, not only can we distinguish Caucasians from Africans and Asians, we can also sort out different groups within Caucasians.

Isn't it amazing that scientists can do this when there's no genetic differences between races?

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Price, V. et al. (2007) Discerning the ancestry of European Americans in genetic association studies. PLoS Genet. In press. [doi:10.1371/journal.pgen.0030236.eor]

Judgment Day Online

 
Judgment Day is the PBS Nova show about the Dover trial. You can now watch it online in 12 episodes [Judgment Day].

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[Hat Tip: Monado at Science notes ( "Intelligent Design on Trial" comes to your computer)]

A World Without Writers

 

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[Hat Tip: Canadian Cynic]

Monday's Molecule #52

 
Today's molecule is a bit more complicated than some. Most of you probably haven't encountered it in your studies and those who have may have seen it drawn a bit differently. Your task is to give it a complete biochemical name as well as the shortened common name.

There's a direct connection between this molecule and Wednesday's Nobel Laureate(s).

The reward goes to the person who correctly identifies the molecule and the Nobel Laureate(s). Previous winners are ineligible for one month from the time they first collected the prize. There are three ineligible candidates for this week's reward. The prize is a free lunch at the Faculty Club.

Send your guess to Sandwalk (sandwalk(at)bioinfo.med.utoronto.ca) and I'll pick the first email message that correctly identifies the molecule and the Nobel Laureate(s). Correct responses will be posted tomorrow along with the time that the message was received on my server. I may select multiple winners if several people get it right.

Comments will be blocked for 24 hours. Comments are now open.

UPDATE: We have a winner! The molecule is 3-hydroxy-3-methylglutaryl-Coenzyme A, or HMG-CoA. Wait to see who the Nobel Laureate is tomorrow.

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Crystal Tells Us about the Human Genome

According to the YouTube profile ...

Crystal is graduated from Texas A&M University w/ a degree in agricultural leadership and development with an emphasis on genetics and bio-chemistry. She is currently a professional model.

Here's her website [crystalnicole.com]. There's not much on her website about DNA or genomes. On the other hand, there's a lot of Crystal. I suspect science isn't her main interest in life.

This is a video about the human genome. Crystal tells us lots of interesting things about the size of our genome, number of genes, junk DNA, whether the DNA of different races is the same etc. etc.

It makes my blood boil. A lot of the information is basically correct but there's no explanations. For example, we know why the rice genome has more genes than the human genome—it's not a mystery. Some of the information is wrong (e.g., similarities between different species). Some of it is misleading (e.g., the definition of a gene).

I assume that this is just a regurgitation of things that Crystal learned in class. Rather than detail all of the errors I'll leave it up to you. You can list them in the comments.

The question I want answered is whether this sort of video serves a useful purpose or not. Is it better to have such a thing on YouTube than nothing at all? (I think we can all agree that the ideal situation would be to have a similar video that was accurate.)

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[Hat Tip: Curious Cat and ScienceRoll]

John Wilkins Likes Sociobiology

 
Wilkins is reviewing a soon-to-be-published paper by David Sloan Wilson and Edward O. Wilson [The two Wilsons on sociobiology]. These two are on a recent tear promoting a new, acceptable, version of group selection. John Wilkins declares that, "I have recently (i.e., in the last five years) come to be an unflinching sociobiologist ..."

This may raise some eyebrows but, as usual, John threads his way through the minefield of misconceptions about sociobiology to arrive at a position that he can support. (I don't agree with him, but that debate is for another time.)

What I particularly like about John's posting is how he separates evolutionary psychology from sociobiology by pointing out the deep flaws in the discipline of evolutionary psychology.

Evolutionary psychology has two major flaws in my opinion. One is that it is almost always adaptationist even when no evidence of adaptiveness is available. Adaptation is, as G. C. Williams noted of group selection explanations, an onerous hypothesis, to be supported or not used. It is too easy to come up with "possible scenarios", let alone possible adaptations. Such explanations need to follow the evidence rather than use, as EvPsych does, a priori arguments from the self-evident truth of natural selection and the nature of evolution.

The second major flaw relates to this. On the (a priori) assumption that selection always favours modularity, EvPsychologists claim that most of the human behavioural repertoire and its underlying neurology is modular. Each module is, as the literature has it, "informationally encapsulated and domain specific", which roughly means that it does one thing well and only that thing, without hints from the rest of our cognitive and sensorimotor system.

I agree with John 100%, although I might add one or two other flaws. I'm not sure the Wilsons would agree, however. I wonder if John knows whether E.O. Wilson is as opposed to evolutionary psychology as he (John) is?

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Where Was Anderson Cooper?

 
The latest death toll from Bangladesh is 2200 and this number will almost certainly rise. Chris Mooney knew this was coming last Wednesday and he warned everyone to expect a disaster [Still No Weakening for Cyclone Sidr].

Why didn't CNN dispatch its crack team of hurricane reporters to the scene? And why, even now, is the news media treating this so lightly?

Yesterday I watched while the CNN anchors reported on the dead and injured and the millions of people who lost their homes. They then switched immediately to light-heated banter about elderly women playing basketball. We didn't see that kind of insensitivity during Katrina, did we?

Should there be a difference just because one hurricane is killing Americans while another is killing people in Bangledesh?


UPDATE: Death Toll Might Reach 10,000.

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[Photo Credits: AFP: Bangladesh cyclone dead number 2,200, millions destitute]

Adaptationist Award #2

 
Jonathan Eisen at The Tree of Life has just given out his second adaptationist award. This "award" goes to those who exemplify the famous Dr. Pangloss referred to in Gould and Lewontin (1979).

This award goes to David Brown for his article in the Washington Post. An article that begins with ...

It used to be a rule -- actually, more of an assumption -- that the genetic machinery of living organisms was never intentionally wasteful or inaccurate. It turns out this isn't always true, either.

I think you can already see why this award is so richely deserved but if you're still in doubt check out the posting [Adaptationomics Award #2 - Washington Post and David Brown].

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Gould, S.J. and Lewontin, R.C. (1979) The Spandrels of San Marco and the Panglossian Paradigm: A Critique of the Adaptationist Programme. Proc. Roy. Soc. (London) Series B, 205:581-598. [OnLine Version]

John Dennehy's Citation Classic

 
John Dennehy's citation classic for this week is a paper by Volkin and Astrachan published in 1956. That's Elliot "Ken" Volkin on the left.

I was not aware of this paper but John makes a good case for its importance in the history of molecular biology. Volkin and Astrachan deserve more recognition for discovering messenger RNA (mRNA). Get on over to The Evilutionary Biologist and read about the private meeting between Francis Crick, Sidney Brenner, and François Jabob in Brenner's room at King's College in 1960 [This Week's Citation Classic].

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[Photo Credit: Oak Ridge National Laboratory]