Do I really need to say how awesome Malate Synthase is?

Part I:  Malate Synthase Looks Amazing


Symmetry is overrated.  It's pretty, but overrated.  Predators, on the other hand, are not overrated.  They are scary, dangerous, and awesome.  We devote weeks of television to them...

Watch me do awesome things!

We make movies about them...

Don't make me angry

Countries use predators in their symbols to show how awesome and tough they are...

OK, this isn't too intimidating.

This is.

So what is the point of all this?

Yes, this is malate synthase. (spheres PDB: 3CUX)

Maybe you don't see it yet...

Paint is one thing I'm not awesome at.

OK, so it's dead.  It still looks crazy scary.

That's right.  Malate synthase looks just like a piranha!  How awesome is that?

Part II:  Malate Synthase Does Awesome Stuff

Not only does malate synthase look like a predator, it helps make predators dangerous in real life.  Cellular predators like bacteria and fungi need to be as efficient as possible in various environments.  Malate synthase makes this possible by completing the glyoxylate cycle pictured below.

Malate synthase catalyzes the reaction in the middle taking glyoxylate to malate in the reaction (1) ...

acetyl-CoA + H₂O + glyoxylate <=> (S)-malate + CoA

This critically bypasses the two carbon dioxide releasing steps of the citric acid cycle and conserves those two carbons with another acetyl group as a second malate.  This can then be used in gluconeogenesis or other synthetic cycles to get even more energy.  When these predators are on the prowl, malate synthase production increases to meet the increased energy demands as the bacteria or yeast attacks the host (2).

The ultimate predator, humans, can also benefit from this energetic advantage bacteria gain from malate synthase and the glyoxylate shunt.  Since it is only important in the attacking organisms and not the host, drugs which block malate synthase activity return the advantage to the hosts in the battle for cellular supremacy (1, 2).

Part III:  Michael Bay wants to make movies about Malate Synthase

We may not look alike, but we do the same thing.

So that might be an exaggeration, but malate synthase is important in a critical transformation for the fungus involved in Penicillium marneffei infection.  It is a delicately tuned transformer appearing as a harmless mycelium at room temperature and transforming into a lethal yeast infection at body temperatures.  Malate synthase is upregulated during this transformation perhaps to supply the necessary energy to promote the lethal change (3).

Part IV:  Conclusion

So, what makes a protein awesome?  Is it lots of pretty helices or barrels?  Is it a really critical function?  Or does it need some almost mythical abilities?  

Malate synthase is all of these.  It looks like a predator, acts like a predator, and even helps transforms harmless organisms into virulent assassins.   Enough said.

One more gratuitous predator pic

Part V:  I am not making this up (Sources)

(1)  Lohman, Jeremy R., Andrew C. Olson, and S. J. Remington. "Atomic resolution structures of Escherichia coli and Bacillus anthracis malate synthase A: Comparison with isoform G and implications for structure-based drug discovery." Protein Sci. 17.11 Nov. (2008): 1935-45.

(2)  Dunn, M. F., J. A. Ramírez-Trujillo, and I. Hernández-Lucas. "Major roles of isocitrate lyase and malate synthase in bacterial and fungal pathogenesis." Microbiology 155 (2009): 3166-75.

(3)  Vanittanakom, Nongnuch, Chester R. Cooper, Jr., Matthew C. Fisher, and Thira Sirisanthana. "Penicillium marneffei Infection and Recent Advances in the Epidemiology and Molecular Biology Aspects." Clinical Microbiology Reviews 19.1 Jan. (2006): 95-110.

In the News!

You may not know this but I've been in the news a bit recently for all the good I do for organisms as small as bacteria and could do for people like you.


Check out this article.


Lohman, Jeremy R., Andrew C. Olson, and S. J. Remington. "Atomic resolution structures of Escherichia coli and Bacillus anthracis malate synthase A: Comparison with isoform G and implications for structure-based drug discovery." Protein Sci. 17.11 Nov. (2008): 1935-45.


Notes on Structure and Reaction Pathway:
This will tell you all you want to know about my structure if you so desire, but I want to focus on some other topics.  The article tells how I am important in the virulence of many bacteria and fungi including Mycobacterium tuberculosis and Candida albicans.  As a part of the glyoxylate shunt, I help avoid the portion of the TCA cycle which gives off carbon dioxide by taking isocitrate directly to malate.  My part of the pathway is the reaction

acetyl-CoA + H₂O + glyoxylate <=> (S)-malate + CoA

The benefit to you people is that you don't have my wondrous enzyme, so even though you are missing out on the benefits you can make drugs to inhibit me so those fungi and bacteria can't enjoy the benefits either.  Taking away my biosynthetic advantages would seriously hamper their virulence, but I think its just jealousy!

One hint to get you started, my A isoform is regulated by acetate and fatty acids while my G isoform is inhibited by glyoxylate, so you may want to start working on their analogs.  Finally, to end on a structural note, my active site is contained within a α8/β8 (TIM) barrel.

More on Virulence and Pathway:

Here is another article which gives more details on the virulent benefits and glyoxylate bypass shunt.

Dunn, M. F., J. A. Ramírez-Trujillo, and I. Hernández-Lucas. "Major roles of isocitrate lyase and malate synthase in bacterial and fungal pathogenesis." Microbiology 155 (2009): 3166-75.

 They included this nice figure showing the pathway.

They also go into more detail about the pathway and include some information on how I effect virulence.  According to these researchers, my presence as part of the glyoxylate shunt allows bacteria, fungi, and plants to use two carbon compounds like acetyl-CoA to synthesize four carbon dicarboxylic acids which can then be used for gluconeogenesis or other biosynthetic pathways.  This is essential for survival in the host organisms.  It also allows TCA cycle intermediates to be replenished or increased as necessary.

Some other trivia from this article include the following.  I, as a part of the glyoxylate pathway, am essential for the growth of plant seedlings since I am part of the pathway which allows stored lipids to be converted to carbohydrates.  I also may have functions as an adhesin and biomarker as recent studies into my effect on M. tuberculosis pathogenicity have shown.

One More:

Vanittanakom, Nongnuch, Chester R. Cooper, Jr., Matthew C. Fisher, and Thira Sirisanthana. "Penicillium marneffei Infection and Recent Advances in the Epidemiology and Molecular Biology Aspects." Clinical Microbiology Reviews 19.1 Jan. (2006): 95-110.

This article is about Penicillium marneffei infection, an opportunistic infection in HIV infected patients in  Southeast Asia.  It is a fungal infection which has the advantage of being able to live as a mycelium at 25°C and as a yeast at 37°C which makes it particularly virulent.  It causes fatal systemic mycosis  in those it infects.  My role in the process is in the yeast phase.  Researchers have found that I am up regulated in the first 20 minutes or so of infection suggesting I have a role in infection in the yeast phase.

Some New Pictures

Here are some pictures of me from my trips in various NMR and X-ray spectroscopes.

Here I am sporting some nice Magnesium ions (green spheres)!  You're getting a great view of my active site there in the middle and the picture is color-edited in PyMOL to show off the cartoon structure by secondary structure (PDB:  3CUX).

This is my best piranha pose (sorry you have to imagine the tail).  It features my surface as spheres with the same color scheme as before (PDB:  3CUX).

Here I'm wearing the flashy chainbows color scheme.  My sequence starts in the bottom right with the little tail of dark blue and follows the colors of the rainbow in reverse order of ROY G. BIV to the red helix in the middle.  Trying out the white background so you can see all those colors! (PDB:  3CUX)

Here I am with my twin.  Each of us is featuring two Mg ions with an oxalate ion bound to the central ion, as well as a CoA.  The color scheme is by chain showing that we are each one chain. (PDB:  3CV2)

This picture is an attempt to show off the residues around the active site.  The Magnesium ion has been colored orange and the green atoms are carbons.  The rest follows the traditional color scheme for elements. (PDB:  3CUX)