Holding Up A Mirror To Nature: Designing A Designer

Nature has evolved with great diversity and vastness of its territories from a simple virus to complex eukaryotes. But, with these complexities it has also left some firing questions and fascinating answers. Despite biology’s variety in complexity and complexity in variety, biochemical machineries of all known biological organisms are homochiral in nature, L-amino acid containing proteins and D-sugar containing nucleic acids. Although there are some exceptions, including D- amino acids in bacterial peptidoglycan, L-arabinose in plants, etc.

Also, biological existence of other form of life is not even challenged by any known chemical or physical rule. This integrity of condition put a firing question in front of us, that how such parallel mirror-image world having other chiral forms of molecular machineries hasn’t been selected in course of evolution. In accordance to answer, efforts has started to create a mirror-image cell step by step. But, every step on path to making mirror cell is blocked by the absence of right protein tool. The molecules that make DNA, DNA polymerases can’t string the mirror-image nucleotides in nucleic acids.

Translation of those mirror-image genes into enzymes? The protein machine that makes RNA from those genes, RNA polymerases. Also, normal ribosomes aren’t in shape to read mirror-image RNA and string together mirror-image amino acids. Although studies have shown possible replication and transcription using very basic systems, without supplementary factors, due to limitations of chemical synthesis of proteins. But, more and more efficient systems are necessary to understand such interguining questionable phenomenon of nature. Hence, to make a concrete blow to these problems together, mirror-image ribosome synthesis would break bottleneck in construction of mirror-image cell.

Recent advances in synthetic organic chemistry have made it possible to chemically synthesize biological macromolecules, such as peptides and nucleic acids of near-arbitrary chirality, revealing the essential properties of mirror-image enzymes and nucleic acids, such as their chiral substrate specificity and biochemical properties that mirror those of their natural counterparts. In solid phase peptide synthesis (SPPS), owing to the accumulation of resin bound by-products, peptides longer than 50 residues are often difficult to synthesize directly. Thus, the native chemical ligation (NCL) method was developed to ligate short peptide segments into longer ones through native peptide bonds. Using peptide hydrazides as thioester surrogates, the synthesis of D-amino acid peptides as long as 312 residues has been demonstrated (Zheng, J. S, et al. 2013).

Also, a thermostable polymerase containing 358 D-amino acids is largest chemically synthesized protein reported to date. Now these, specific piece of information opens gate for chemical synthesis of ribosome. Although complex, but with exception of ribosomal protein S1, which is expendable for the translation of leaderless mRNA (Moll, I. et al., 2004), most of the ribosomal proteins are no longer than 240 amino acids, which makes them suitable candidates for the complete chemical synthesis. Subunit no. UniProt accession of protein Subunit no.

Every step on path to making mirror cell is blocked by the absence of right protein tool. Synthesis of mirror-image ribosome will led to more efficient and sophisticated machineries of a complex nature than chemical synthesis. Also, there is many more things with answering a burning question of evolution. Mirror-image nucleic acid and peptides has shown more stability and efficacy as therapeutic tool. Hence, these breaking bottlenecks with this kind of work will offer more therapeutic opportunities faster and cheaper.

REFERENCES:

1. Jewett, M. C., Fritz, B. R., Timmerman, L. E., & Church, G. M. (2013). In vitro integration of ribosomal RNA synthesis, ribosome assembly, and translation. Molecular systems biology, 9(1), 678.
2. Moll, I., Hirokawa, G., Kiel, M. C., Kaji, A., & Bläsi, U. (2004). Translation initiation with 70S ribosomes: an alternative pathway for leaderless mRNAs. Nucleic acids research, 32(11), 3354-3363.
3. Pech, A., Achenbach, J., Jahnz, M., Schülzchen, S., Jarosch, F., Bordusa, F., & Klussmann, S. (2017). A thermostable d-polymerase for mirror-image PCR. Nucleic acids research, 45(7), 3997-4005.
4. Wang, Z., Xu, W., Liu, L., & Zhu, T. F. (2016). A synthetic molecular system capable of mirror-image genetic replication and transcription. Nature chemistry, 8(7), 698.
5. Zheng, J. S., Tang, S., Qi, Y. K., Wang, Z. P., & Liu, L. (2013). Chemical synthesis of proteins using peptide hydrazides as thioester surrogates. Nature protocols, 8(12), 2483.