Phosphorylation

Phosphorylation attaches a phosphate group to the hydroxyl of a serine, threonine or tyrosine side chain; kinases install it using ATP and phosphatases remove it, so in a living cell it is transient and reversible. Each phosphate adds 80 daltons and roughly two negative charges at physiological pH, enough to switch an enzyme on or off. In written notation the residue appears as pSer, pThr or pTyr, or with a parenthetical phosphate after it.

In this field phosphorylation matters mostly as the downstream event, not the drug. Insulin and IGF-1 receptors autophosphorylate on tyrosine, growth hormone acts through JAK2 phosphorylating STAT5, and muscle protein synthesis studies read out phosphorylated Akt and mTOR as evidence a pathway was engaged. Deliberately phosphorylated peptides are chiefly research tools; the casein phosphopeptides of milk used in dental products are a rare consumer example.

Phosphopeptides are seldom drugs because the phosphate is both labile and impermeable: phosphatases strip it quickly and its charge keeps the peptide out of cells. Drug designers use non-hydrolysable mimics instead, such as phosphonomethyl-phenylalanine for phosphotyrosine. In synthesis the residue is coupled as a protected building block, since adding phosphate afterwards is unselective.

The misreading is the phospho-blot presented as an outcome. A rodent study showing a stronger band for phosphorylated Akt after a peptide reports that a pathway was touched for minutes to hours, not that muscle was gained, and the same band appears after a meal or a bout of exercise. A listing that calls a growth-factor mimetic a phosphopeptide has confused a peptide that is phosphorylated with one that phosphorylates something else.