Amino Acid Chirality

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TimD
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Amino Acid Chirality

Postby TimD » Sat Nov 13, 2010 4:48 pm UTC

So, in the vast majority of polypeptides, we find only L amino acids. Why?

A good wikipedia session, and a good deal of reading from MBoC sheds little light on the subject. So far I know that all D form amino acids that are used (eg peptidoglycan) are so formed by post-translational modification of the polypeptide, and that all amino acids used in the ribosome are L form. I recall being told in various ways that the translation process is stereospecific, but what I can't find is which bit it is. My gut feeling is that it must have something to do with the aminoacyl tRNA synthases that do it, they're the only step in translation that are properly specific to the amino acid, you can put the wrong amino acid on a tRNA and it doesn't mind (but the error correction enzymes do). I can't however, find anything to back up this point of view.

Anyone able to help me out?

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Re: Amino Acid Chirality

Postby Meteorswarm » Mon Nov 15, 2010 1:27 pm UTC

(I'm guessing this is homework)

What kind of molecules can distinguish chiral molecules?
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Re: Amino Acid Chirality

Postby BlackSails » Mon Nov 15, 2010 3:55 pm UTC

I believe this is actually an open question.

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Re: Amino Acid Chirality

Postby TimD » Mon Nov 15, 2010 4:02 pm UTC

Stems from a homework question, but I got interested in exactly how the chirality is preserved. I know it's an enzyme, hence my suggestion that it is the aminoacyl tRNA synthase enzymes that do it, as they're the ones that bind the amino acid to the tRNA (ie only bind Val, and not Leu), hence they're specific to the amino acid and tRNA that they bind. What I couldn't find any information on is whether they are specific to the chirality of the amino acid (only bind L-Val and not D-Val). An alternative hypothesis would be that the amino acid synthase enzymes will only produce L amino acids. I couldn't find a study testing this (eg by supplying an extracellular protein synthesis system consisting of only the aminoacyl tRNA synthase enzymes, tRNA's amino acids and ribosomes (and plenty of ATP etc) and then observing to see if proteins with a mixture of D and L amino acids were formed.).

Edit: Just spotted your post there BlackSails. Given the silence around it everywhere I looked I sort of assumed that there was no definitive answer. Should in theory be a fairly easy experiment to do, using the method set out above. I've seen references to similar studies used to test the effects of various enzymes.

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Re: Amino Acid Chirality

Postby BlackSails » Mon Nov 15, 2010 4:09 pm UTC

Well, there is the trivial answer - amino acids are L because their metabolic pathways produce L. But the real question I think is why are they L instead of D? Why do the enzymes produce and act on L amino acids (and D sugars) instead of the other way around?

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Re: Amino Acid Chirality

Postby Mr_Rose » Mon Nov 15, 2010 6:51 pm UTC

BlackSails wrote:Well, there is the trivial answer - amino acids are L because their metabolic pathways produce L. But the real question I think is why are they L instead of D? Why do the enzymes produce and act on L amino acids (and D sugars) instead of the other way around?

Especially given that the natural geochemistry we assume created the first amino acids, simple sugars, and nucleotides all, as far as I remember, shows no particular chiral preference.
My mol. bio. tutor (back in ought-four) attributed this mostly to blind luck; that is, at some point it became more efficient to only produce (and re-cycle) one form of each major monomer than to have multiple sets of enzymes to do the same job but with different components and as such one set* was "picked" for some reason we don't understand fully and that choice is what we've stuck with ever since.
I don't really know whether the state of the art on this particular topic has advanced much since then though.



* Given the almost limitless perfusion of 'possible' amino acids, almost all of which have stereoisomers, the fact that early life on Earth stuck with twenty to thirty of them, all with what would later be recognised as the same chirality, might be held to suggest that there was something special about those particular ones. However, nothing I know of makes them particularly special beyond the fact that they are the ones we use.
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Re: Amino Acid Chirality

Postby justaman » Mon Nov 15, 2010 7:26 pm UTC

I suspect that substituting a D-amino acid for an L- isomer, would result in conformational changes at the secondary and tertiary structure of the protein, which I suspect (can anyone confirm?) is where the evolutionary pressure would apply.
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Re: Amino Acid Chirality

Postby Izawwlgood » Mon Nov 15, 2010 8:02 pm UTC

My guess is if you somehow managed to recreate the protein from the L- form, instead of the D-, you'd just end up with a mirror image of your protein. AFAIK, the decision to use the D-form carries no advantage, but L-form amino acids are entirely ignored by every biological process. My guess is a few residue replacements with the L-form would be acceptable, but could easily disrupt integral protein function depending on location.
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Re: Amino Acid Chirality

Postby TimD » Mon Nov 15, 2010 8:05 pm UTC

BlackSails wrote:Well, there is the trivial answer - amino acids are L because their metabolic pathways produce L. But the real question I think is why are they L instead of D? Why do the enzymes produce and act on L amino acids (and D sugars) instead of the other way around?

Another interesting question is why we don't use both, with the two stereoisomers coded for by different codons. Things like this make evolution any biology generally a bit more fun. You can't think of anything biological simply as it is now, you have to consider everything and everywhere it's ever been to make any sense of it. In the immortal words of Dobzhansky, nothing in biology makes sense except in the light of evolution.

My guess is if you somehow managed to recreate the protein from the L- form, instead of the D-, you'd just end up with a mirror image of your protein. AFAIK, the decision to use the D-form carries no advantage, but L-form amino acids are entirely ignored by every biological process. My guess is a few residue replacements with the L-form would be acceptable, but could easily disrupt integral protein function depending on location.
Not as simple as that, the mirror image thing only works for one chiral centre, with more than one things rapidly become more complex.

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Re: Amino Acid Chirality

Postby Izawwlgood » Mon Nov 15, 2010 8:09 pm UTC

TimD wrote:Another interesting question is why we don't use both

Because synthesizing enzymes to operate on two things is more work than making enzymes that only operate on one.
TimD wrote:Not as simple as that, the mirror image thing only works for one chiral centre, with more than one things rapidly become more complex.

I was thinking that, but I'm not sure. I'd wager that you simply end up with the mirror image. Basic secondary structures are still kosher, they're just reversed.
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Re: Amino Acid Chirality

Postby BlackSails » Mon Nov 15, 2010 8:34 pm UTC

There is a paper somewhere on the arxiv, where the authors lay out a possible mechanism -

All neutrinos in nature are left-handed. Now assume there is some (very weak) coupling between the orientation of nuclear spin of N14 and what stereoisomer it is part of. Its possible for a neutrino to interact with the nucleus of N14 to cause it to decay, making the molecule no longer an amino acid. Over cosmic time scales, you end up with a chiral imbalance, which is then amplified.

Sort of far fetched, but its not the worst idea I have ever heard.

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Re: Amino Acid Chirality

Postby TimD » Mon Nov 15, 2010 9:19 pm UTC

BlackSails wrote:There is a paper somewhere on the arxiv, where the authors lay out a possible mechanism -

All neutrinos in nature are left-handed. Now assume there is some (very weak) coupling between the orientation of nuclear spin of N14 and what stereoisomer it is part of. Its possible for a neutrino to interact with the nucleus of N14 to cause it to decay, making the molecule no longer an amino acid. Over cosmic time scales, you end up with a chiral imbalance, which is then amplified.

Sort of far fetched, but its not the worst idea I have ever heard.

Not absurd, but will definitely need some work to prove. What is an interesting field is the work into the reproducibility of evolution, I know a few postgrads doing work into that now, using an error prone from of PCR to generate mutations, then playing theses alleles out against each other with arbitrary fitness criteria, selecting the fittest, reproducing, mutating and repeating.

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Re: Amino Acid Chirality

Postby Mick7153 » Mon Nov 15, 2010 9:46 pm UTC

Izawwlgood wrote:
TimD wrote:Another interesting question is why we don't use both

Because synthesizing enzymes to operate on two things is more work than making enzymes that only operate on one.

This right here is the reason. It takes too much energy. Proteins and enzymes are the shape they are because they follow thermodynamics, and are at the lowest energy. Which in turn is why anything with L-chirality makes L-amino acids, its not as much energy or work.

If we're going all the way back.... couldn't say. Perhaps it just happened to be favored?

Chirality is not something that can be mixed easily, as it changes the chemical properties rather radically
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Re: Amino Acid Chirality

Postby Izawwlgood » Mon Nov 15, 2010 9:52 pm UTC

You know, out of curiosity;
Assuming an RNA world; it's possible that simple peptides that interacted with RNA utilized a chirality that interacted with the nascent rotation of dsRNA... I mean, I'm grasping at straws here, but it seems there's possibly SOME preference in orientation of structure here due to the configuration of nucleic acid helices. Admittedly, protein structures can be created, via either L- or D-forms, to interact with helices of either turn orientation... so, I dunno, nevermind that.
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Re: Amino Acid Chirality

Postby Mr Pete » Mon Nov 15, 2010 10:40 pm UTC

chirality doesn't really affect the reactivity unless other chiral things are involved (as is the case here so that is irrelevent).

using the opposite enantiomers of amino-acids would probably alter the protein's structure. Disulphide bridges (between cysteine? It has been a while...) effectively make ring structures (huge, complicated ones, but rings nevertheless). Multiple chiral centres on a ring makes it a diastereomer, leading to different chemical properties between the cis/trans forms.

I remember reading something a while back, some theoretical calculations including the weak nuclear force found that the natural amino acids are slightly more favoured (to a tiny degree, but that might be all it took). But the calculations are disputed.

Take this post with a hefty dose of salt, for I am le tired.

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Re: Amino Acid Chirality

Postby qetzal » Tue Nov 16, 2010 7:43 pm UTC

Proteins made from D-amino acids are indeed mirror images of their L-amino acid counterparts. You can't make D-amino acid proteins enzymatically (AFAIK), but you can do it chemically by peptide synthesis. You can only make fairly small proteins that way, however.

People are actually exploiting this to do some interesting science & drug development. For one example, see this paper (pdf).

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Re: Amino Acid Chirality

Postby Agent_Irons » Fri Nov 26, 2010 7:53 am UTC

I like that neutrino idea, if only because literally very little else makes any sense. Separating enantiomers chemically is a PITA, because the two enantiomers are chemically identical except for stuff like crystallization. Only L instead of L and R is easy to see: All amino acids have the same chassis(well, except a couple, run with me here), so attaching the side chains is easier if you only have to do it to one side.

So why L instead of R? There is probably no answer. Flip a coin. Why is it the answer it is? It just is.

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Re: Amino Acid Chirality

Postby pietertje » Fri Nov 26, 2010 3:03 pm UTC

I remember reading somewhere in my biochemistry textbook that D-aminoacids form less stable alpha-helices and seeing how alpha-helices are the most common secondary structures, it would be logical to assume that natural selection favoured the more stable structure.

I have no idea if this is true, the book only devoted like 3 lines to this subject. I'll see if I can find it again.

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Re: Amino Acid Chirality

Postby rflrob » Sat Nov 27, 2010 8:09 pm UTC

Mick7153 wrote:
Izawwlgood wrote:
TimD wrote:Another interesting question is why we don't use both

Because synthesizing enzymes to operate on two things is more work than making enzymes that only operate on one.

This right here is the reason. It takes too much energy. Proteins and enzymes are the shape they are because they follow thermodynamics, and are at the lowest energy. Which in turn is why anything with L-chirality makes L-amino acids, its not as much energy or work.

If we're going all the way back.... couldn't say. Perhaps it just happened to be favored?

Chirality is not something that can be mixed easily, as it changes the chemical properties rather radically


It seems to me that if you could synthesize lots of D-amino acids, you could run a long term evolution experiment a-la Lenski et al, where you had a minimal medium supplemented with lots of D-amino acid. Anything that learned to efficiently use the synthetic amino acids ought to have a huge selective advantage.

And yes, I realize that the scope of what I'm proposing is actually huge. Maybe with robotics it could be made less onerous than the current LTE experiment, but probably not by a whole lot, in the grand scheme of things.
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Re: Amino Acid Chirality

Postby Izawwlgood » Sat Nov 27, 2010 8:16 pm UTC

rflrob wrote:And yes, I realize that the scope of what I'm proposing is actually huge. Maybe with robotics it could be made less onerous than the current LTE experiment, but probably not by a whole lot, in the grand scheme of things.

The scope is huge, but not because of a lack of robotics.
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