Curcumin (Curry Could Cure Cancer?)
22nd May 2006
This is the yellow pigment in turmeric, the spice responsible for curries being nuclear holocaust yellow.
It has attracted some interest lately because it is a possible anticancer compound (Fang, et al. “Thioredoxin Reductase Is Irreversibly Modified by Curcumin”, J. Biol. Chem. (2005) 280:25284-25290). Thioredoxin reductase is an enzyme that reduces thioredoxin, an important reducing enzyme in your body. Confused? Biochemistry can be that way. Typically, Nature is pretty parsimonious, but for reasons of specificity and regulation, you will sometimes see funny pathways like this.
For the purposes of this article, though, let’s just think of it as an important enzyme. One critical cancer drug target is DNA synthesis. Drugs like AZT target this. Since cells really only need to make DNA when they’re dividing, rapidly dividing cells like cancer are preferentially targeted. Since thioredoxin reductase is needed to reduce thioredoxin, which is needed to provide reducing equivalents to ribonucleotide reductase to prepare deoxyribonucleotides in DNA, cancer cells tend to overexpress it.
Curcumin is an enone and can tautomerize into a charge-separated compound. The selenate and thiolate residues in thioredoxin reductase can react irreversibly with it. Here is the first addition:
The arrow denotes the flow of an electron pair. It’s actually a Michael Addition, for which the mechanism is often drawn like that.
Here is the addition product.
A second addition occurs, yielding this inactivated enzyme. The selenium and sulfur atoms are crucial to many redox enzymes like thioredoxin reductase’s activity. The destruction of the enzyme induces apoptosis.
Curcumin is a surprisingly nontoxic chemical for being a potential chemotherapeutic skeleton. Healthy individuals in India and other countries ingest upwards of half a gram a day with no ill effects. Curcumin inhibits irreversibly at at around 10 micromolar; that dose is within striking distance of that concentration.
This is all speculative stuff — the mechanism I’ve given isn’t actually proven! It is a pretty likely addition product though. The Michael addition is a well-characterized and versatile piece of organic synthesis. As you might imagine, the molecule can mess with other enzymes, and it does, sometimes to good effect, sometimes otherwise. Curcumin as an anticancer agent is the kind of thing you’d see written up as a puff piece on curry curing cancer in USA Today. It’s a possibility, that’s all so far. I mainly decided to write it up because I really like pleasingly symmetric molecules!
Also unique to curcumin is selenocysteine, which is a selenium analogue of cysteine, and a rare amino acid. It’s a neat molecule in its own right, which we’ll get into sometime.