Monday, March 1, 2010

B Fwd: Metamodern Ribo-Q1: Genetic manufacturing expanded

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Date: Mon, Mar 1, 2010 at 4:30 AM
Subject: Metamodern (1 new item)

Metamodern (1 new item)

Item 1 (03/01/10 06:17:59 UTC): Ribo-Q1: Genetic manufacturing expanded

Unnatural amino acids
Unnatural amino acids compatible with ribosomes
(circled: azide, alkyne,
and biotin derivative)

From Neumann et al., 2010 and Dougherty, 2000.

All ribosomes read genetic data as three-letter words that encode 20 standard amino acids (give or take a few anomalies). This is equally true of the ribosomes in deep-sea bacteria living at 120°C, and the ones in your thumb. This universal code has been a wall that bounds the scope of biosynthetic polypeptide engineering — until now.

Recent developments have cracked the wall by tweaking the code, but Jason Chin's group in the UK has blasted a wide hole by expanding the address space.

From the abstract of a paper soon to be published in Nature:

[E]very triplet codon in the universal genetic code is used in encoding the synthesis of the proteome….Here we synthetically evolve an orthogonal ribosome (ribo-Q1) that efficiently decodes a series of quadruplet codons…. By creating mutually orthogonal aminoacyl-tRNA synthetase–tRNA pairs and combining them with ribo-Q1 we direct the incorporation of distinct unnatural amino acids…. it will be possible to encode more than 200 unnatural amino acid combinations using this approach.

H Neumann et al., "Encoding multiple unnatural amino acids via evolution of a quadruplet-decoding ribosome", Nature (early online publication).

I've selected some examples (image above) to illustrate the scope of these methods. Each of these amino acids (some highly unnatural) has already been used as a building block in ribosomal polypeptide synthesis. Together, they provide a glimpse of the vast new world now opening to molecular engineers. Polypeptides (of the sort usually called "proteins") are already a family of versatile, high-performance engineering polymers, and an expanded set of building blocks can be exploited to increase thermodynamic stability, extend useful functionality, facilitate self assembly, and enable more systematic design.

Realizing this potential for expanding the scope of protein engineering will require extensive development of new tools, including new aminoacyl-tRNA synthetase–tRNA pairs. Because these are themselves proteins, there will be increasing opportunities for bootstrapping, using the new tools to facilitate development of those that follow. For example, could task-specific side chains (perhaps PNA oligomers) facilitate the development of new aminoacyl-tRNA synthetases?

By the way, even the amide bond in the backbone isn't sacred: ribosomes happily make esters, too. Unlike enzyme-like, substrate-specific catalysts, ribosomes are machines for positioning reactants bound to handles. Their substantial generality is characteristic of handle-based mechanosynthetic catalysis.
See also:

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