Evolution of Protein Structures
Part II
Part II. Evolution of Proteins/Enzymes with More Complex Functionality
Some proteins are more complex in structure because their function is more complex.
Dehydrogenases are good examples of enzymes involved in metabolism that are more complex than a simple protein like Cytochrome c. Dehydrogenases are enzymes transferring electrons from a reduced substrate to NAD+ -- a cellular electron carrier. Although it is not too important to our discussion, the structure of NAD+ and its reduced form NADH is shown below:
Figure 7. The structure of NAD+ and NADH.
We will look at 3 different dehydrogenases (alcohol dehydrogenase, lactate dehydrogenase, and glyceraldehyde-phosphate dehydrogenase) which all use NAD+ as an electron acceptor, but use different metabolites as the reduced substrate which donates the electrons to NAD+ making it into NADH:
Figure 8. Reactions catalyzed by 3 Dehydrogenases: A) Alcohol Dehydrogenase; B) Lactate Dehydrogenase; and C) Glyceraldehyde-Phosphate Dehydrogenase.
Alcohol dehydrogenase is the enzyme in your liver which converts ethanol into acetaldehyde during metabolism. This is the reason that excess alcohol consumption causes problems with your liver since it is difficult to get rid of acetaldehyde which is very reactive and can cross-link proteins in your liver.
Lactate dehydrogenase is the enzyme in your muscles involved in anaerobic metabolism which helps keep your muscles working under limited oxygen stress.
Glyceraldehyde-phosphate dehydrogenase is a key enzyme in glycolysis in your liver and other tissues and also a very important enzyme in photosynthesis in green plants.
These 3 dehydrogenases are divided into two subparts called domains. One domain is for binding the unique substrate of the enzymes (ethanol, lactate or glyceraldehyde-phosphate - sometimes called GAP), while the other domain is for binding NAD+.
Figure 9. 3-D model of GAP dehydrogenase showing the NAD+ bound to the enzyme. This enzyme has only one polypeptide chain and it is clearly divided into the two subparts, which we call domains. Green domain binds GAP substrate, while Red domain binds NAD+.
Figure from Voet, Biochemistry - copyright 1990 John Wiley & Sons
In each of the 3 dehydrogenases, both the NAD+ and other substrate binding sites are in the same polypeptide so these two parts are called domains. Similar 3-D shapes are found for the NAD+ binding site and domain in these 3 dehydrogenases.
Figure 10. NAD+ domains of the 3 dehydrogenases: A) Alcohol Dehydrogenase; B) Lactate Dehydrogenase; and C) Glyceraldehyde-Phosphate (GAP) Dehydrogenase. Note the similarity of the shape of each of these NAD+ domains.
Drawings of these domains by Jane Richardson who owns the copyright.
The other substrate (ethanol, lactate or glyceraldehyde-phosphate) are bound by different shapes.
Figure 11. Reducing substrate domains for the 3 dehydrogenases: A) Alcohol Dehydrogenase; B) Lactate Dehydrogenase; and C) Glyceraldehyde-Phosphate (GAP) Dehydrogenase. Note the different shape of each of these substrate binding domains.
Drawings of these domains by Jane Richardson who owns the copyright.
While all these NAD+ domains have the same shape only a few key AA are same and AA sequences different. Thus, it is possible to get the same shape for a domain of a protein with the same function using a different AA sequence. The AA sequence of the NAD+ domain is changed to make it fit to the other domain for the unique reducing substrate of each of these 3 dehydrogenases.
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©Wilbur H. Campbell, 1995; wcampbel@mtu.edu