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| | <b>Molecular Tour</b><br> | | <b>Molecular Tour</b><br> |
| - | The source of diversity in life is a parallel diversity in the atoms of DNA - add a few atoms here, take some away there, and behold! the lion had become a lamb. Proteins, the main building stuff of life, are the primary recipients of changes in DNA atmos: fiddle with DNA, increase the diversity of proteins, of life. But how does an old protein morph into a new one? How does a protein that is comprised of thousands of atoms, change as a result of changes in a few DNA atoms?
| + | Figure 1. General mechanisms for the hydrolysis of the three classes of rePON1 substrates: |
| | + | the lactones (A), the esters (B) and the phosphotriesters (C). The 2HQ inhibitor and additional |
| | + | substrate molecules are presented (D). |
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| - | Farmers in the 1960s were using a man-made pesticide called “parathion” that interferred with insects’ nervous systems. But the 1980s, scientists had found that some bacteria on these farms contained an paraoxanse enzyme, they called Phosphotriesterase (PTE) for eating this pesticide. How did the bacteria evolve this enzyme in just a few decade? The recent paper by Ben David et al. (JMB, 2012) of the Weizmann Institute offers a compelling explanation for the evolution of paraoxon-metabolizing enzymes in a short period, and their explanation begins to explain how the tweaking of atoms in DNA has resulted in the glorious diversity of life.
| + | Figure 3. Changes in the rePON1 binding site upon binding of 2HQ. Superimposition of the |
| - | | + | rePON1-2HQ complex (cyan;; the closed conformation) with the apo rePON1 structures at pH |
| - | The discovery several years ago that a lactonase enzyme they called Quarom quenching lactonase (QQL) was the parent of the novel PTE, as demonstrated by similar fold, active site configuration, and sequence, was an exciting first step. The lab had since demonstrated that a lactonase from mammals (PON1) (shown - helix, beta sheet and active site) can be turned into a paraoxanase by changing just one amino amino acid (shown) By analogy, understanding how PON1 becomes a paraoxonase will likely explain the natural evolution of QQL to PTE.
| + | 4.5 (orange) and pH 6.5 (blue) (the open conformations). The pH 4.5 conformation prevents |
| - | | + | closure of the active-site loop due to clashes of F347 and H348 with the loop residues (e.g. |
| - | PON1 uses more than one amino acid (shown - H115 and E53) to achieve a single function (serving as bases for activating a water to become a nucleophile), and this the researchers think is key to PON1 becoming a paraoxanse. Lactone, the intended substrate of PON1, is the right shape to make use of both H115 and E53 (shown), but paraoxon has a similar but not identical shape, and can only take advantage of E53 (shown). But because the bacteria has an enzyme with already some paraoxon activity, it only needs to tweak the protein to achieve higher paraoxon activity, and tweaking DNA can accomplish just that. The use of two amino acids to do one function enables similar but not identical molecules to use even one amino acid to achieve that function. One amino acid at least gives paraoxon a “hand-hold” on the protein that facilitates further evolution. The key to evolution is additive distribution of one function between amino acids. Thus, a non-native molecule can at least make use of one amino acid. And natural selection takes over from there.
| + | F77 and I74). Also illustrated is the movement of Y71 (dashed arrow) upon binding of 2HQ, |
| - | | + | and its interaction with D183 in the 2HQ complex structure. |
| - | Importantly, in a world fearful of chemical warfare, Paroxonase can be used to prevent nerve agents like paroxon from mortally damaging a person’s nervous system.
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Revision as of 15:45, 6 March 2012
Title Of The Paper
Authors[1]
Molecular Tour
Figure 1. General mechanisms for the hydrolysis of the three classes of rePON1 substrates:
the lactones (A), the esters (B) and the phosphotriesters (C). The 2HQ inhibitor and additional
substrate molecules are presented (D).
Figure 3. Changes in the rePON1 binding site upon binding of 2HQ. Superimposition of the
rePON1-2HQ complex (cyan;; the closed conformation) with the apo rePON1 structures at pH
4.5 (orange) and pH 6.5 (blue) (the open conformations). The pH 4.5 conformation prevents
closure of the active-site loop due to clashes of F347 and H348 with the loop residues (e.g.
F77 and I74). Also illustrated is the movement of Y71 (dashed arrow) upon binding of 2HQ,
and its interaction with D183 in the 2HQ complex structure.
- ↑ none yet
