(''S'')-3,5-Dihydroxyphenylglycine or DHPG is a potent

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of group I metabotropic glutamate receptors (mGluRs) mGluR1 and

mGluR5 Metabotropic glutamate receptor 5 is an excitatory Gq-coupled G protein-coupled receptor predominantly expressed on the postsynaptic sites of neurons. In humans, it is encoded by the ''GRM5'' gene. Function The amino acid L- glutamate is the ...

. DHPG was the first agonist shown to be selective for group I mGluRs. Agonist activity is found in only the (''S'')-

isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. Iso ...

, and (''S'')-DHPG may be a partial agonist of group I mGluRs. (''S'')-DHPG has been investigated for therapeutic effects in the treatment of neuronal injury (such as those associated with

ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...

hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...

), cognitive enhancement, and

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

. 3,5-Dihydroxyphenylglycine can be isolated from the latex of '' Euphorbia helioscopia''. DHGP is also found in vancomycin and related glycopeptides. Although the (S) stereoisomer is synthesized by the DpgA-D enzymes, it is the (R) stereoisomer that is used in vancomycin and other related compounds. DHPG is enzymatically derived from the polyketide synthase pathway.

Biosynthesis

When synthesized in bacteria, DHPG requires 5 enzymes, DpgA-D and 4-hydroxyphenylglycine transferase (Pgat), in order to be synthesized. DpgA is a type III polyketide synthase and initiates the synthesis by condensing

acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...

with three molecules of

malonyl-CoA Malonyl-CoA is a coenzyme A derivative of malonic acid. Functions It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis. Fatty acid biosynthesis Malonyl-CoA provides 2-carbon units to fatty acids and commi ...

. The tetra-carbonyl compound then cyclizes to form a C8 intermediate. DpgB/D then dehydrates the intermediate using enolate chemistry to promote the loss of water. DpgB/D isomerizes the product to aromatize the ring. DHPG_biosynthesis_part_1

DpgC oxidizes the aromatic intermediate at the benzylic carbon using oxygen to an alpha-keto compound. DpgC performs this oxidation in absence of any iron, heme, flavin, or pterin cofactors. Chen ''et al'' suggest the following reaction mechanism to explain the reactivity of DpgC. This mechanism is supported by findings reported in Widboom ''et al'' in 2007.Widboom, P. F., Fielding, E. N., Liu, Y., Bruner, S. D. "Structural basis for cofactor-independent dioxygenation in vancomycin biosynthesis." ''Nature'', 2007, ''447'', 342-345. Finally, the molecule is transaminated by 4-hydroxyphenylglycine transferase using tyrosine to become DHPG. DHPG_biosynthesis_part_3

4-Hydroxyphenylglycine transferase synthesizes the (S) stereoisomer of DHPG, however, an epimerase switches the stereocenter to the (R) configuration after DHPG is incorporated into the vancomycin non-ribosomal polypeptide.

References

{{Non-proteinogenic amino acids Amino acid derivatives Nootropics Resorcinols MGlu1 receptor agonists MGlu5 receptor agonists Non-proteinogenic amino acids