HomeLatest ThreadsGreatest ThreadsForums & GroupsMy SubscriptionsMy Posts
DU Home » Latest Threads » Forums & Groups » Topics » Science » Science (Group) » A wonderful place to cons...

Wed Aug 30, 2017, 10:13 PM

A wonderful place to consider the interface of RNA catalysis and enzyme catalysis.

Sometimes I like to drift around in the scientific literature and learn about things about which I know little, or about which I haven't thought for a long time.

Many years ago - quite a long time ago - I used to play around with amino acid chemistry making some lovely messes of things as well as some very beautiful and interesting compounds that actually went commercial on a large industrial scale.

Anyway, back in the late 1980's Thomas Cech and Sidney Altman were awarded the Nobel Prize in chemistry for their discovery of the catalytic properties of RNA, which lead to much speculation about a prebiotic (or neobiotic) "RNA world" wherein life arose not as suggested in the famous Miller experiment, but rather from RNA. (It is known that the basic constituents of RNA, purines and pyrimidines, as well as some simple sugars not all that far from ribose are found in interstellar clouds.)

Over the years, I've been intrigued by origin of life and the related issue of the origin of chirality.

In my stumbles today, I came across an interesting recent review of something which I was unaware, the role of amino acid acylated tRNA in the synthesis of certain natural products with very complex structures and a wide array of precisely ordered chiral centers. (Chirality is the property of something which cannot be superimposed on its mirror image, the most convenient example being two hands on a person.)

For example, here is the structure of the natural product ergotamine, from which one can obtain (by hydrolysis) lysergic acid, the precursor of the notorious drug LSD:

If one looks at this molecule with an organic chemist's eye and one is also familiar with the twenty proteinaceous amino acids, one can see that the part of the system (the four fused ring portion that is the core of lysergic acid) can be derived from the amino acid tryptophan by self acylation of the benzo ring, followed by conversion of a resulting keto function into a double bond as part of a cyclization process, a process that one can certainly engineer relatively easily in a lab. Similarly, one can identify in the three fused ring system in the ergotamine molecule a possibly phenylalanine derived portion, a proline portion and an alanine portion. (I actually have no idea about the actual biosynthesis of this molecule.)

We see some very complex natural products of extreme importance to humanity, the total synthesis of which remains even in these times synthetically inaccessible. Examples include the core of taxanes, an important class of cancer drugs, as well as many complex antibiotics like for instance, vancomycin, which clearly involves tyrosine and phenylalanine origins:

And so it I'm wandering through this very beautiful review, which examines the role that the catalytic activity of acyl RNA plays in the biosynthesis of these important molecules: Aminoacyl-tRNA-Utilizing Enzymes in Natural Product Biosynthesis (Mireille Moutiez†, Pascal Belin†, and Muriel Gondry, Chem. Rev., 2017, 117 (8), pp 5578–5618).

The review article - which I've not finished reading yet - is very interesting, and although I don't see where it offers any speculations on the origin of life and the role of RNA in creating the protein carbohydrate world in which we now live, it thrills the imagination.

Some stuff from the introductory text:

...aa-tRNAs are ubiquitous molecules originally identified as the compounds responsible for delivering amino acids for the mRNA-guided synthesis of proteins at the ribosome. They function as adaptors between the mRNA codons and the growing polypeptide chain.1−3 They are composed of a tRNA of about 80 nucleotides in length attached to an aminoacyl moiety consisting of a single amino acid. Several bases constituting the tRNA undergo species-specific posttranscriptional modifications that are important for folding, stability, translational efficiency, and fidelity, and for diverse regulatory processes4, 5 (Figure 1a). The tRNA part of the molecule has a characteristic cloverleaf secondary structure that folds into an L-shaped tertiarystructure6−8 (Figure 1a, b). One end of the L-shaped molecule carries the trinucleotide anticodon that specifically interacts with mRNA codons by base pairing, whereas the other end bears the attachment site for the cognate amino acid. Amino acid attachment is catalyzed by specific aminoacyl-tRNA synthetases (aaRSs) in a two-step reaction.9...

...The enzymes of the glutamyl-tRNA reductase family reduce the aminoacyl moiety of Glu-tRNAGlu to form glutamate1-semialdehyde, the first precursor in the biosynthesis of tetrapyrroles such as hemes and chlorophylls.29−31 Enzymes from other families catalyze modification of the aminoacyl moiety of aa-tRNAs (i.e., while this moiety is still attached to tRNAs) to generate aa-tRNAs loaded with asparagine, glutamine, formylmethionine, cysteine, or selenocysteine.15,32 The past decade has seen the identification of new aa-tRNA-dependent enzyme families, all of which are involved in the biosynthesis of microbial secondary metabolites,33−40 referred to hereafter asNPs (Figure 2).

A fascinating read...

Esoteric I know, but of interest certainly to chemists and biochemists.

7 replies, 2982 views

Reply to this thread

Back to top Alert abuse

Always highlight: 10 newest replies | Replies posted after I mark a forum
Replies to this discussion thread
Arrow 7 replies Author Time Post
Reply A wonderful place to consider the interface of RNA catalysis and enzyme catalysis. (Original post)
NNadir Aug 2017 OP
Docreed2003 Aug 2017 #1
Warpy Aug 2017 #2
NNadir Aug 2017 #3
TxDemChem Aug 2017 #4
NNadir Aug 2017 #5
TxDemChem Sep 2017 #6
NNadir Sep 2017 #7

Response to NNadir (Original post)

Wed Aug 30, 2017, 10:25 PM

1. Fascinating read...

Thanks for forcing me to dust off the memory banks to remember my molecular genetics/organic/biochem!

Reply to this post

Back to top Alert abuse Link here Permalink

Response to NNadir (Original post)

Wed Aug 30, 2017, 10:31 PM

2. Since you're interested in RNA, the origin of life, and literate

in skullcracking, jawbreaking prose, you might be interested in this: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332834/

I know I was delighted when I found it and other similar articles as I've always thought viruses, especially retroviruses, have played a part in discontinuous evolutionary patterns.

Reply to this post

Back to top Alert abuse Link here Permalink

Response to Warpy (Reply #2)

Wed Aug 30, 2017, 10:43 PM

3. Why thank you. That is indeed an interesting article. Recently I've had some involvement...

...projects utilizing AAV viruses - or more properly their viral coats - as vehicles for gene therapy.

This of course, is different than the interesting paper you shared, since a quick scan of the paper you offered indicates that the viral genome as well as its vehicle.

Never heard of it before now.


Reply to this post

Back to top Alert abuse Link here Permalink

Response to NNadir (Original post)

Thu Aug 31, 2017, 08:13 PM

4. Sounds very fascinating

You actually made tRNA a lot more interesting than it was in college.

Reply to this post

Back to top Alert abuse Link here Permalink

Response to TxDemChem (Reply #4)

Thu Aug 31, 2017, 09:14 PM

5. You know, for most of my life I've been a peptide/protein kind of guy, at least so far as...

...medicinal chemistry goes, since for much of my career I've worked with peptidomimetics, which actually has bearing on the OP in this thread.

You get to thinking that that is where all the action is.

I while back I ran across a wonderful text, called The Sugar Code because I was looking into the issue of glycans as post translational modifications of, um, proteins and I was struck by the depth and importance of glycomics about which I'd actually thought very little.

Like most of the books you actually end of reading, it has a captivating opening:

Teaching the biochemistry of carbohydrates is not simply an exercise in terminology. It has much more to offer than commonly touched upon in basic courses, if we deliberately pay attention to the far-reaching potential of sugars beyond energy metabolism and cell wall stability. In fact, then there is no reason why complex carbohydrates should shy at competition with nucleic acids and proteins for the top spot in high-density biocoding. On the contrary, sugars have ideal properties for this purpose, as will be concluded at the end of this chapter. In this sense, an obvious explanation why research in glycosciences (structural and functional glycomics and lectinomics) has lagged behind the fields of genomics and proteomics, also in the public eye, is 'that glycoconjugates are much more complex, variegated, and difficult to study than proteins and nucleic acids' [1]. What is a boon for decorating cell surfaces with a maximum number of molecular messages at the same time has been and still is a demanding challenge for analytical and synthetic chemistry (please see Chapters 3-5 for details on how to address it properly).

Put another way, people don't pay attention to the roles of sugars because sugar chemistry is hard.

You just have to go forward in a book like that.

I confess, I wasn't much interested in nucleic acid biochemistry either, until at least I attended a "Science on Saturday" lecture at the Princeton Plasma Physics lab by Shirley Tilghman, the former President of Princeton University, who got tired of all that administrator stuff and went back to the lab.

The lecture is on line: PPPL Science on Saturday lecture: The Wild and Wacky World of Epigenetics

A little while later I found myself begging a technical guy at a major mass spec company to offer software to dig post translational modifications of nucleic acids, some equivalent of say, Sciex's Protein Pilot.

(He personally agreed with me, but it ain't happened yet.)

It may happen that nucleic acid chemistry will end up being as important in therapeutics as proteins and the related ADC's (antibody drug conjugates) are now. There are certainly some companies betting on that. I've recently had the pleasure of working with some folks on revivified gene therapy programs. They're powerfully intriguing. It would be wonderful if they proved viable. Lives would be saved.

Nucleic acid biochemistry, in which I am in no way an expert, I believe, must be fascinating. If I don't run out of time in my life, I'd love to understand it more deeply. I'm coming to understand, if not on a profound level of deep knowledge, how beautiful it is.

Reply to this post

Back to top Alert abuse Link here Permalink

Response to NNadir (Reply #5)

Fri Sep 1, 2017, 05:48 AM

6. Thanks for the lecture and book links

I'm going to have to check them out soon. I've always found carbohydrates to be intimidating and perhaps not worth the effort, but I think you're on to something.

Hopefully someone other than you and the tech guy will see value in that software.

Reply to this post

Back to top Alert abuse Link here Permalink

Response to TxDemChem (Reply #6)

Fri Sep 1, 2017, 06:06 AM

7. Oh believe me, that software will happen. I'm a relatively low level guy, but the big guys...

...definitely appreciate the need for it.

Some of the problem derives from the fact that there's a habit of thinking that nucleic acids are all about and only about coding. Another is the habit of addressing the analytical issues and synthetic issues associated with nucleic acids with PCR and qPCR.

That's why I found the review in the paper in the OP so exciting. It's really not about coding at all; it's about catalysis.

Relatively late in life I've become a mass spec acolyte. It is the most incredibly powerful tool, particularly when matched with software. Recently I've seen mass spec software that can do in a half hour what used to take graduate students years to do. The technical guy with whom I chatted on the phone for an hour or so was hired by his company to talk to guys like me. He gets it, and I'm sure his company will get it. They're an innovative bunch and will succeed, at least if science isn't executed in this country by the ignorance that's become fashionable in our Congress and Executive branch.

Reply to this post

Back to top Alert abuse Link here Permalink

Reply to this thread