Why uracil?

ColoradoSkiBum said:

Hi all

For those of you who are familiar with the mechanism of protein synthesis, I'm wondering what could
possibly be the evolutionary advantage of the substitution of uracil for thymine in RNA?

Thymine(T) is just uracil(U) with a methyl group. The problem is that cystosine(C) will deaminate
to form uracil at some rate. If DNA used uracil, there would be no way to determine if a U in a
sequence was correct or just a deaminated C. By having T in DNA, proofreading enzymes can safely
convert all found U's to C's, since every U in DNA has been created by the deamination of a C.
RNA is used in a more temporary way than DNA and tolerates this rate of C deamination to U.
William L Hunt

Quoted message said:

--
ColoradoSkiBum

ColoradoSkiBum said:

Hi all

For those of you who are familiar with the mechanism of protein synthesis, I'm wondering what could
possibly be the evolutionary advantage of the substitution of uracil for thymine in RNA?

I suggest the loss of the methyl group in uracil changes the activity level of the adjacent
carbonyl. This allows differences in reactivity that was useful for the evolution of RNA and its
subsequent functions.

James Michael Howard

<< Hi all

For those of you who are familiar with the mechanism of protein synthesis, I'm wondering what could
possibly be the evolutionary advantage of the substitution of uracil for thymine in RNA?
--
ColoradoSkiBum

Quoted message said:

Quoted message said:

I am only an amateur but I would suggest one reason is "Thymine dimer' UV can damage Thymine and
make a dimer between adjacent thymines that distorts the helix.

At the beginning of the earth there was a period of high UV, with no ozone layer. Uracil would have
an advantage over thymine at that time.

Note that uracil is in RNA which came before DNA which has thymine.

Tom Hendricks

[email hidden] (William L Hunt) wrote in message news:<[email hidden]>...

Quoted message said:

ColoradoSkiBum said:

Hi all

For those of you who are familiar with the mechanism of protein synthesis, I'm wondering what
could possibly be the evolutionary advantage of the substitution of uracil for thymine in RNA?

Thymine(T) is just uracil(U) with a methyl group. The problem is that cystosine(C) will deaminate
to form uracil at some rate. If DNA used uracil, there would be no way to determine if a U in a
sequence was correct or just a deaminated C. By having T in DNA, proofreading enzymes can safely
convert all found U's to C's, since every U in DNA has been created by the deamination of a C.
RNA is used in a more temporary way than DNA and tolerates this rate of C deamination to U.
William L Hunt

Quoted message said:

--
ColoradoSkiBum

Dear SkiBum, You may have noticed that Mr. Hunt answered a different question than you asked. He
explained the evolutionary advantage of substituting thymine for uracil in DNA. His morphing of your
question is probably right - current thinking is that RNA came first. However, Mr. Hunt's
explanation cannot be the whole story. For one thing, there is a chicken-egg problem with which came
first - the methyl groups or the proofreading mechanisms that use the methyls. The full story is not
yet known, but it is probably interesting and involves early chemical warfare. For some hints of
what might have happened, you should research restriction enzymes and GC post-replication
methylation of C in many species. Jim Menegay

James Michael Howard <[email hidden]> wrote in message news:<[email hidden]>...

Quoted message said:

ColoradoSkiBum said:

Hi all

For those of you who are familiar with the mechanism of protein synthesis, I'm wondering what
could possibly be the evolutionary advantage of the substitution of uracil for thymine in RNA?

I suggest the loss of the methyl group in uracil changes the activity level of the adjacent
carbonyl. This allows differences in reactivity that was useful for the evolution of RNA and its
subsequent functions.

James Michael Howard

The question of when and how is almost as interesting as why. Thymine almost certainly was used by
the last common ancestor. But the likely suspects as methyl donors - folate and corrinoids - are
different in the methanogens and perhaps other archaea. So what was donating the methyl to de-oxy
uracil in the LCA? What else did this altruist donate to? Methionine probably. Can anyone else think
of other methyl recipients in the LCA? I'd like to know what was the first methyl group donor and
methyl group receiver in the history of life. Was the first methyl transfer reaction orchestrated by
a ribozyme or a protein enzyme? My "gut" tells me that this is not the sort of reaction that a
ribozyme would be good at. But, in that case, did Methionine get added to the code after translation
was already up and running? It seems odd that you would change the amino acid of the start codon.

Are there co-enzymes that absolutely require methylation before they can work? Don't some of the
electron transport chain carriers have methyls attached by ether bonds, presumably to make them
lipid soluble? Are there pigments that need methyls to work properly? Are any of these plausible as
the first methyl receiver?

When I see a reaction like methylation of uracil, which must have been already happening before it
came to be used as a clue in proofreading, my usual suspicion is that the metabolism "wanted" to add
the methyl group to something else, but ended up adding it to uracil too, because it wasn't specific
enough. The trouble with that theory, here, is that nothing else that "should have gotten" the
methyl looks anything like uracil. But then maybe I don't perceive things in the way that a near-
sighted enzyme would.

On Fri, 12 Dec 2003 00:22:16 +0000 (UTC), [email hidden]

(Jim Menegay) said:

James Michael Howard <[email hidden]> wrote in message
news:<[email hidden]>...

Quoted message said:

ColoradoSkiBum said:

Hi all

For those of you who are familiar with the mechanism of protein synthesis, I'm wondering what
could possibly be the evolutionary advantage of the substitution of uracil for thymine in RNA?

I suggest the loss of the methyl group in uracil changes the activity level of the adjacent
carbonyl. This allows differences in reactivity that was useful for the evolution of RNA and its
subsequent functions.

James Michael Howard

The question of when and how is almost as interesting as why. Thymine almost certainly was used by
the last common ancestor. But the likely suspects as methyl donors - folate and corrinoids - are
different in the methanogens and perhaps other archaea. So what was donating the methyl to de-oxy
uracil in the LCA? What else did this altruist donate to? Methionine probably. Can anyone else
think of other methyl recipients in the LCA? I'd like to know what was the first methyl group donor
and methyl group receiver in the history of life. Was the first methyl transfer reaction
orchestrated by a ribozyme or a protein enzyme? My "gut" tells me that this is not the sort of
reaction that a ribozyme would be good at. But, in that case, did Methionine get added to the code
after translation was already up and running? It seems odd that you would change the amino acid of
the start codon.

My "gut" feeling is the use snoRNAs in mediating the methylation of rRNA is a carryover of the RNA
world with only the methylase no longer being a ribozyme. If true this means there was some
controlled use of methylation in the RNA world. Also I expect Methionine was available, but I don't
think the 'early code' necessarily used Methionine or even a start codon as such. The sequence
before the start codon is what positions the ribosome and initially may have been all that was
needed to start translation. A start codon would just tweak the positioning so there was no initial
frame shifting. William L Hunt ... [snip] ...

[email hidden] (William L Hunt) wrote in message news:<[email hidden]>...

Quoted message said:

(Jim Menegay) said:

... I'd like to know what was the first methyl group donor and methyl group receiver in the
history of life. Was the first methyl transfer reaction orchestrated by a ribozyme or a protein
enzyme? My "gut" tells me that this is not the sort of reaction that a ribozyme would be good at.
But, in that case, did Methionine get added to the code after translation was already up and
running? It seems odd that you would change the amino acid of the start codon.

My "gut" feeling is the use snoRNAs in mediating the methylation of rRNA is a carryover of the
RNA world with only the methylase no longer being a ribozyme. If true this means there was some
controlled use of methylation in the RNA world. Also I expect Methionine was available, but I
don't think the 'early code' necessarily used Methionine or even a start codon as such. The
sequence before the start codon is what positions the ribosome and initially may have been all
that was needed to start translation. A start codon would just tweak the positioning so there was
no initial frame shifting. William L Hunt

It looks like my "gut" must yield here, as your "gut" is better informed. I had not know that
snoRNA's were involved in methylations. I agree that it looks likely that RNA may have been involved
in both specifying and catalysing this reaction in the RNA world. Your comments re Met also seem
reasonable.

That is unwelcome news to me. It means that I have no possible justification for "pretending" that
folate coenzymes did not appear until after translation. I had hoped to construct a model of RNA
world metabolism, but if folate is available as a universal source of C1 units, the problem is
completely unconstrained. Rybozymes COULD HAVE manufactured anything. There is no longer any
credible way to argue that my list is what they DID manufacture.

But, even though you have crushed my dreams, thanks anyways. Have a nice day. ;-)

Jim M.

On Wed, 17 Dec 2003 18:21:38 +0000 (UTC), [email hidden]

(Jim Menegay) said:

[email hidden] (William L Hunt) wrote in message news:<[email hidden]>...

Quoted message said:

(Jim Menegay) said:

... I'd like to know what was the first methyl group donor and methyl group receiver in the
history of life. Was the first methyl transfer reaction orchestrated by a ribozyme or a protein
enzyme? My "gut" tells me that this is not the sort of reaction that a ribozyme would be good
at. But, in that case, did Methionine get added to the code after translation was already up and
running? It seems odd that you would change the amino acid of the start codon.

My "gut" feeling is the use snoRNAs in mediating the methylation of rRNA is a carryover of the
RNA world with only the methylase no longer being a ribozyme. If true this means there was some
controlled use of methylation in the RNA world. Also I expect Methionine was available, but I
don't think the 'early code' necessarily used Methionine or even a start codon as such. The
sequence before the start codon is what positions the ribosome and initially may have been all
that was needed to start translation. A start codon would just tweak the positioning so there
was no initial frame shifting. William L Hunt

It looks like my "gut" must yield here, as your "gut" is better informed. I had not know that
snoRNA's were involved in methylations. I agree that it looks likely that RNA may have been
involved in both specifying and catalysing this reaction in the RNA world. Your comments re Met
also seem reasonable.

That is unwelcome news to me. It means that I have no possible justification for "pretending" that
folate coenzymes did not appear until after translation. I had hoped to construct a model of RNA
world metabolism, but if folate is available as a universal source of C1 units, the problem is
completely unconstrained. Rybozymes COULD HAVE manufactured anything. There is no longer any
credible way to argue that my list is what they DID manufacture.

I think most of the ribozyme labs think ribozymes could do almost but not quite everything that
protein enzymes can do. There are many reasons to think the genetic code preceded DNA but one
would be the inability of ribozymes to do the -OH to -H catalyse. A quote from one source: "The
possibility that RNA could catalyze a free radical reaction seems unlikely, therefore protein was
needed before ribonucleotide reductase could exist and therefore before DNA could be made."
William L Hunt

[email hidden] (William L Hunt) wrote in message news:<[email hidden]>...

Quoted message said:

I think most of the ribozyme labs think ribozymes could do almost but not quite everything that
protein enzymes can do. There are many reasons to think the genetic code preceded DNA but one
would be the inability of ribozymes to do the -OH to -H catalyse. A quote from one source: "The
possibility that RNA could catalyze a free radical reaction seems unlikely, therefore protein was
needed before ribonucleotide reductase could exist and therefore before DNA could be made."
William L Hunt

I've seen that argument before, and it has always puzzled me. I agree that having a ribozyme work
with radicals is implausible. And, I understand that the modern enzymes doing this job all use
radicals. But what is there about the difficulty of this reaction that makes the use of free
radicals necessary?

As I look through my biochemistry text, it seems that -OH is being changed to -H all the time by
standard two-electron reductions. (Though, I admit, many of those cases seem to proceed by
dehydrating before reducing.) Is it the presence of the base at the 1' position that makes the usual
methods impossible and forces the use of a free radical mechanism? If so, why not make deoxy-ribose
before you add or build the base?

Jim