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

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of group I

metabotropic glutamate receptor The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic receptor, metabotropic process. They are members of the group C GPCR family, group C family of G-protein-coupled r ...

s (mGluRs)

mGluR1 The glutamate receptor, metabotropic 1, also known as GRM1, is a human gene which encodes the metabotropic glutamate receptor 1 (mGluR1) protein. Function L-Glutamate is the major excitatory neurotransmitter in the central nervous system and ...

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 formula – that is, the same number of atoms of each element (chemistry), element – but distinct arrangements of atoms in space. ''Isomerism'' refers to the exi ...

, and (''S'')-DHPG may be a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of group I mGluRs. (''S'')-DHPG has been investigated for therapeutic effects in the treatment of

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

al 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 ...

or hypoxia), cognitive enhancement, and

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. 3,5-Dihydroxyphenylglycine can be isolated from the latex of ''

Euphorbia helioscopia ''Euphorbia helioscopia'', the sun spurge or madwoman's milk, is a species of flowering plant in the spurge family Euphorbiaceae. It is a herbaceous annual plant, native to most of Europe, northern Africa, and eastward through most of Asia.''Flor ...

''. DHGP is also found in

vancomycin Vancomycin is a glycopeptide antibiotic medication used to treat certain bacterial infections. It is administered intravenously ( injection into a vein) to treat complicated skin infections, bloodstream infections, endocarditis, bone an ...

and related

glycopeptide Glycopeptides are peptides that contain carbohydrate moieties ( glycans) covalently attached to the side chains of the amino acid residues that constitute the peptide. Over the past few decades it has been recognised that glycans on cell surf ...

s. 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 In organic chemistry, polyketides are a class of natural products derived from a Precursor (chemistry), precursor molecule consisting of a Polymer backbone, chain of alternating ketone (, or Carbonyl reduction, its reduced forms) and Methylene gro ...

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 oxidation, o ...

with three molecules of

malonyl-CoA Malonyl-CoA is a coenzyme A derivative of malonic acid. Biosynthesis Malonyl-CoA cannot cross membranes and there is no known malonyl-CoA import mechanism. The biosynthesis therefore takes place locally: * cytosol: Malonyl-CoA is formed by c ...

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