The Sixth Nitrogenous base in Bacteriophage

A nitrogenous base (n-base) is a nitrogen-containing organic molecule that functions as a base in chemical processes. N-bases are also known as nucleobases because they are essential components of the nucleic acids i.e. Deoxyribonucleic acid (DNA) and Ribonucleic acid (RNA). RNA transforms DNA into proteins to carry out biological operations, while DNA provides the code for the cell’s actions. The primary or canonical nucleobases are Adenine (A), Guanine (G), Cytosine (C), Thymine (T) and Uracil (U). The nucleotides A, G, T, C are found in DNA while A, G, C, U are found in RNA. They serve as fundamental components of the genetic code.

With more than 10³¹ in population bacteriophages are the biosphere’s most common and diverse organisms. A bacteriophage, often known as phage, is a virus that infects bacteria and archaea and replicates within them. They either have a DNA or RNA genome that is encased in a protein capsule. Their genomes can code for as few as four genes (eg. MS2) or as many as hundreds.

A study conducted in Russia quite 40 years ago led to the invention of cyanophage S-2L, a kind of bacteriophage that replaces the DNA building block Adenine, commonly called A, with 2-aminoadenine, denoted Z. However, the rationale for the phage’s substitution of A with Z was never investigated until recently within last 20 years. Two distinct groups of scientists have uncovered how viruses generate and build Z into their genetic instructions, and one reason they are doing so, in step with articles published within the journal, Science.

Synthesis of 2-aminoadenine (Z):

Philippe Marliere, a xenobiologist at the Pasteur Institute in Paris at that time came across the 1977 Russian research reporting the cyanophage with the unique DNA. Then Marliere with his colleagues obtained a sample of the virus and decrypted the phage’s whole set of genetic instructions, or genome. The researchers discovered instructions for generating an enzyme called PurZ within the virus’ genome that may do the initial step in making Z, also referred to as Diaminopurine. Thus in 2003, the Pasteur Institute applied for a patent on the enzyme in Marliere’s name.

With the discovery of PurZ, they now knew how Z was synthesized but the method of why A was replaced with Z within the bacteriophage was still within the dark.

Substituting A with Z:

The polymerase of the cyanophage S-2L doesn’t discriminate between A and Z, as per a recent study by Marliere’s partner Pierre Alexandre Kaminski and colleagues, but a viral enzyme called DatZ degrades adenine building blocks, leaving polymerase with no choice but to use Z. Marliere explored genetic databases daily for the other phages with PurZ that may have the elusive finicky polymerase. He discovered that Siphoviridae bacteriophage infecting a large range of bacteria, all have DpoZ polymerase variants that preferentially insert Z instead of A into the viruses’ DNA.

Countermeasure against bacterial defence:

According to Zhau and colleagues, substituting A with Z could be an unconscious process against bacterial restriction enzyme, which slice DNA from invading phages. Z-base containing DNA is difficult for such enzymes to acknowledge and cut. Z forms three hydrogen bonds with thymine, rather than two hydrogen bonds that hold the A-T base pair together. The three hydrogen bonds that hold the Z-T base pair makes it more stable. Z also alters the way DNA curves and bends, possibly making it tougher to pack into small areas than A containing genetic material. It’s also a part of a never-ending race between phages and bacteria, says Steven Benner, a chemist and astrobiologist at the muse for Applied Molecular Evolution in Alachua.

Future prospects:

Everything that helps with reproduction is favoured in the natural part. Survival and reproduction instincts are two qualities that are subjected to the most intense selection pressure. Individuals who were unconcerned about their own survival died before reproducing, removing the genes that caused it from the gene pool. Every individual of every species thrives for one thing: survival. DNA is a tool created by life to sustain life, and losing it would be disastrous. Charles Darwin stated in the nineteenth century that the species that is the fittest among them all with survive. The subservient species had always gone extinct, according to historical data dating back to the genesis of a cell. Bacteriophages have tiny genomes, which explains why they mutate so quickly. The finding of the sixth N-base in bacteriophage is a great example of how life changes to become more powerful and stable. “Life isn’t what we expect it to be,” Floyd Romesberg said. “Life doesn’t have to be GTAC; it may be a lot more interesting.” In a nutshell, the study shows how little we know about bacteriophage genomes, mutations and evolution. Their sophisticated, small machinery, as well as their high mutation susceptibility, is a major research roadblock. Hopefully, this advancement in the field of virology will aid researchers in their studies of virus evolution and lead to the development of new ways to combat them.

References:

1. Sleiman, D., Garcia, P., Lagune, M., Loc’h, J., Haouz, A., & Taib, N. et al. (2021). A third purine biosynthetic pathway encoded by aminoadenine-based viral DNA genomes. Science, 372(6541), 516-520. doi: 10.1126/science.abe6494
2. Todde, V., Veenhuis, M., & van der Klei, I. (2009). Autophagy: Principles and significance in health and disease. Biochimica Et Biophysica Acta (BBA) – Molecular Basis Of Disease, 1792(1), 3-13. doi: 10.1016/j.bbadis.2008.10.016
3. Zhou, Y., Xu, X., Wei, Y., Cheng, Y., Guo, Y., & Khudyakov, I. et al. (2021). A widespread pathway for substitution of adenine by diaminopurine in phage genomes. Science, 372(6541), 512-516. doi: 10.1126/science.abe4882