Organic chemistry under assault

The first is an attempt to remove organic chemistry  from the premed curriculum.  As the math instructor said to the grad students in a course I was auditing, if you want to be an academic mathematician, you’d better like teaching calculus.  It’s the main service course of math departments with lots of people taking it who have no intention of becoming mathematicians.  This means a lot of positions in math departments.  The same probably goes for organic in many chemistry departments.  I’ve written a post on why I think future physicians should be required to take and pass it.   Here’s a link https://luysii.wordpress.com/2009/09/01/why-organic-chemistry-should-always-be-taken-and-passed-by-pre-meds/.

The second assault is the downsizing, outsourcing and general carnage presently taking place in the pharmaceutical industry, particularly affecting medicinal (e.g. organic) chemists.  Anyone of several recent posts on In the Pipeline (and particularly the comments they bring forth) should be enough to convince you.  The most interesting recent one was the one of 10 February along with the 65 comments it engendered (most of which were pretty pessimistic, particularly about the chance of developing a new blockbuster drug).

So I want to address that here, particularly since there isn’t room to put it all in a comment in Derek’s blog.   In what follows I’ll assume you know a fair amount of molecular and cellular biology (something medicinal chemists should know IMHO).  I’m not going to tell you what the disease is, or name the drug used to treat it (not cure it).  That’s for next time.  The exercise will show you just how hard drug discovery is, and why genome wide association studies point in all directions without necessarily leading to a drug.

The disease has been known for years.  Most of it occurs sporadically, but familial cases are known, and several different causative genes have been isolated from these families (long before single nucleotide polymorphisms and genome wide association studies were available).  In addition, several drugs are known to cause symptoms of the disease, and in one awful example a particular drug can result in a permanent state of the disease with severe disability (after just one or two intravenous doses).

This awful drug is transported into the cell and gets into mitochondria, inhibiting complex I of the respiratory chain, and generating reactive oxygen species as well.  Well, cyanide anion also inhibits the respiratory chain, but the remarkable thing about the awful drug is that it doesn’t kill all cells, just a small minority (under 1/100,000) of cells in just one organ.

Several of the genes causing the familial disorder code for proteins found in mitochondria.   One (gene #1) of them is a serine/threonine protein kinase — a beloved target of the pharmaceutical industry.  Overexpression of this protein is protective against apoptosis due to oxidative stress.   The gene product promotes mitochondrial fusion.  One of the phosphorylation targets of the protein is known, but no one knows what it does (in addition, it’s likely that there are more targets).  We do know that the protein spans the outer mitochondrial membrane with the kinase facing the cytoplasm.

Another gene product (gene #2)  has ubiquitin ligase activity, and interestingly, patients with mutations in this gene don’t show the cytoplasmic inclusions seen in the disorder (see later) — so the inclusions might be protective rather than causative (it’s been long assumed that they are causative).  The list of proteins ubiquitinated by gene #2 protein was up to 6 by 1993 and a good deal of work has been done to see what these proteins do.  Initially, ubiquitination was thought to be synonymous with protein destruction, but we know better now — sometimes ubiquitination of a protein just changes its function.

Gene #3 is one of the targets of gene #3 for ubiquitination.  It is one of the main components of the inclusion (which like most inclusions contains many many different proteins).  If I told you where the inclusion is normally found you might figure out what the disease actually, and I want to make this exercise realistic for the process of drug discovery from the ongoing genome wide association studies. Interestingly, the inclusion is found in a different part of the cell than where the protein is normally found.

Gene #4 is the opposite of gene #2 — it removes polymeric ubiquitin from proteins. It is also found in the inclusions of the disorder.

Gene #5 is even more interesting, in that some mutations are oncogenic –however,  the disease I’m describing is NOT a form of cancer.  In animal models, gene #5  protects against oxidative stress.  It binds to a variety of specific mRNA species, explaining its many effects (pleiotropy) but its actual function(s) isn’t/aren’t  known at this time.

Gene #6 is a monster, with over 2500 amino acids.  It is also a protein kinase.  But being this huge, gene #6 contains all sorts of other modules which bind to other proteins (WD40, ankyrin), which hydrolyze GTP.  Interestingly, mutations in this gene have also been associated with sporadic cases of the disease in question.  Most of the gene product is in the cytoplasm but 10% is in mitochondria.

Fairly confusing isn’t it.  I will tell you that the blockbuster drug for this disorder was found long before these genes were discovered, and in a completely different way (in which chemistry was absolutely crucial).  I think this is a fairly realistic description of where the drug discovery process is today.

Anyone who wants the glory of figuring out what the disease and its treatment actually is, please post a comment.

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Comments

  • Wavefunction  On February 15, 2010 at 12:56 am

    This is a shot in the dark but I am guessing schizophrenia and haloperidol

  • Yggdrasil  On February 15, 2010 at 1:24 am

    Parkinsons. The part about a drug causing the disease was the giveaway for me. Gene #2 (parkin?) and the frequent mention of mitochondria helped to confirm my guess. Not sure what the blockbuster drug is though. L-DOPA?

  • Wavefunction  On February 15, 2010 at 6:36 pm

    Damn. I realized after commenting that the mention of “inclusions” would rule out Schizophrenia. I am guessing you are talking about alpha-synuclein inclusions. Which would make the disease likely to be Parkinsons, and as Yggdrasil says, the drug to be L-DOPA. What’s the awful drug? MPTP? Haloperidol? Any one of a number of antiscychotics?

    It’s interesting that a simple *overheating* of MPPP (in which MPTP was originally discovered as a contaminant) in the presence of basic conditions can result in an elimination of the ester, resulting in the deadly MPTP

  • luysii  On February 15, 2010 at 9:58 pm

    9 PM EST 15 Feb ’10

    Last chance to win valuable prizes. Get your entry in before tomorrow evening when all will be revealed.

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