Phosphorylation and Its Role in Biology

Study Notes

Phosphorylation is the addition of a phosphoryl (PO3) group to a molecule.
This is vital for cellular storage and energy transfer in biological systems.
Energy carrier molecules are used in this process.
Phosphorylation produces high-energy phosphodiester bonds, such as those in ATP and GTP.
The body uses these molecules to phosphorylate other molecules, which activates them.

Phosphorylation introduces a leaving group, which can be displaced by an incoming nucleophile.
This is seen in DNA and RNA synthesis, where nucleotides are added to the 3' end of a growing DNA or RNA chain.

Phosphorylation is often required for the activation of antiviral agents.
These agents are often nucleosides that must be converted to nucleotides to be active.
Antiviral agents commonly disrupt DNA or RNA synthesis, typically by converting them to triphosphates.
Some antiviral agents are designed to target viral kinases more effectively than mammalian kinases for increased selectivity and reduced toxicity to healthy cells.

Idoxuridine is a prodrug that shows clinical effectiveness against viruses.
Idoxuridine has higher affinity for viral kinases than mammalian kinases, making it more selective against viruses.
Idoxuridine enters virally infected cells and is phosphorylated preferentially by viral thymidine kinase, making it a superior substrate.
Following phosphorylation, it can inhibit viral DNA synthesis.
- This can happen through several mechanisms including inhibiting viral DNA polymerase.
- It can disrupts the ability of viral DNA/RNA as a template molecule by incorportating into viral DNA, resulting in incorrect base pairing.
Idoxuridine is generally lipid soluble.

Methenamine is a prodrug used for urinary tract antiseptics, functioning as a source of formaldehyde.
The low pH of the urine promotes the hydrolysis to formaldehyde, the active antibacterial agent.
Methenamine serves as a substrate for the enzymes involved in phosphorylating processes in viruses.
The phosphorylated forms of the antiviral agents are the active form.

Site-specific drug delivery is often used with drugs having narrow therapeutic windows (e.g., anticancer drugs).
High metabolic activity in organs like the liver and kidneys offers an advantage for drug delivery.
The rate of conversion from prodrug to active drug at target sites should be greater compared to other areas to limit toxicity.
There should be a slow migration of the active drug from target sites to minimize any side effects that may occur after the drug is no longer needed.
Various carrier systems have been considered to aid drug delivery, including proteins, polysaccharides, liposomes, and implemented mechanical pumps.

The goal is to protect a drug from the non-specific biological environment where it may be rendered inactive before it reaches its target, and to protect a non-specific environment from the drug to prevent unintended harm to healthy cells.
This concept is vital for drugs with a narrow therapeutic window, particularly anti-cancer agents.

Podcast