4-Hydroxyphenylglycine

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4-Hydroxyphenylglycine
HPG figure.png
4-Hydroxyphenylglycine (HPG). (R)-D-HPG shown on left; (S)-L-HPG shown on right.
Names
IUPAC name
Nortyrosine
Systematic IUPAC name
Amino(4-hydroxyphenyl)acetic acid
Other names
3-Amino-2,3,6-trideoxy-3-methyl-L-lyxo-hexopyranose
Identifiers
3D model (JSmol)
513130
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.012.139 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 213-353-2
KEGG
PubChem CID
UNII
  • Key: LJCWONGJFPCTTL-UHFFFAOYSA-N
  • C1=CC(=CC=C1C(C(=O)O)N)O
Properties
C8H9NO3
Molar mass 167.164 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

4-Hydroxyphenylglycine (HPG) is a non-proteogenic amino acid found in vancomycin and related glycopeptides. HPG is synthesized from the shikimic acid pathway and requires four enzymes to synthesize: [1] Both L- and D-HPG are used in the vancomycin class of antibiotics. Tyrosine, a similar amino acid, differs by a methylene group (CH2) between the aromatic ring and the alpha carbon.

Contents

Biosynthesis

Biosynthesis of HPG HPG biosynthesis.png
Biosynthesis of HPG

HPG is synthesized from prephenate, an intermediate in the shikimic acid pathway and also a precursor to tyrosine. Prephenate is aromatized by prephenate dehydrogenase (Pdh) using NAD+ as a cofactor to produce 4-hydroxyphenylpyruvate. 4-Hydroxyphenylpyruvate is then oxidized by 4-hydroxymandelate synthase (4HmaS) using oxygen to form 4-hydroxymandelate and hydrogen peroxide. 4HmaS is a non-heme iron-dependent dioxygenase. The reaction mechanism of this unique oxidation was proposed by Choroba et al in 2000 [2]

Proposed mechanism by Choroba et al for the oxidation of 4-hydroxymandelate. Proposed HmaS mechanism.png
Proposed mechanism by Choroba et al for the oxidation of 4-hydroxymandelate.

4-Hydroxymandelate is subsequently oxidized by hydroxymandelate oxidase (Hmo) to 4-hydroxylbenzoylformate, using FMN as a cofactor. [3] Finally, 4-hydroxyphenylglycine transaminase (HpgT) transfers an ammonia moiety from a donor to 4-hydroxylbenzoylformate to form HPG. Several different molecules can serve as the nitrogen donor for the transamination, however, Hubbard et al suspect L-tyrosine to serve as the most efficient donor. [4] By doing so, the following cycle is constructed:

HPG synthetic cycle HPG synthetic cycle.png
HPG synthetic cycle

HPG is also synthesized in Herpetosiphon aurantiacus using enzymes Haur_(1871,1887,1888). [5]

See also

Related Research Articles

<span class="mw-page-title-main">Tyrosine</span> Amino acid

L-Tyrosine or tyrosine or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Greek tyrós, meaning cheese, as it was first discovered in 1846 by German chemist Justus von Liebig in the protein casein from cheese. It is called tyrosyl when referred to as a functional group or side chain. While tyrosine is generally classified as a hydrophobic amino acid, it is more hydrophilic than phenylalanine. It is encoded by the codons UAC and UAU in messenger RNA.

<span class="mw-page-title-main">Vancomycin</span> Antibiotic medication

Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is used intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant Staphylococcus aureus. Blood levels may be measured to determine the correct dose. Vancomycin is also taken orally as a treatment for severe Clostridium difficile colitis. When taken orally it is poorly absorbed.

<span class="mw-page-title-main">Teicoplanin</span> Pharmaceutical drug

Teicoplanin is an semisynthetic glycopeptide antibiotic with a spectrum of activity similar to vancomycin. Its mechanism of action is to inhibit bacterial cell wall peptidoglycan synthesis. It is used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and Enterococcus faecalis.

<span class="mw-page-title-main">Cysteine dioxygenase</span> Enzyme

Cysteine dioxygenase (CDO) is a non-heme iron enzyme that catalyzes the conversion of L-cysteine to cysteine sulfinic acid. CDO plays an important role in cysteine catabolism, regulating intracellular levels of cysteine and responding changes in cysteine availability. As such, CDO is highly regulated and undergoes large changes in concentration and efficiency. It oxidizes cysteine to the corresponding sulfinic acid by activation of dioxygen, although the exact mechanism of the reaction is still unclear. In addition to being found in mammals, CDO also exists in some yeast and bacteria, although the exact function is still unknown. CDO has been implicated in various neurodegenerative diseases and cancers, which is likely related to cysteine toxicity.

Shikimic acid, more commonly known as its anionic form shikimate, is a cyclohexene, a cyclitol and a cyclohexanecarboxylic acid. It is an important biochemical metabolite in plants and microorganisms. Its name comes from the Japanese flower shikimi, from which it was first isolated in 1885 by Johan Fredrik Eykman. The elucidation of its structure was made nearly 50 years later.

<span class="mw-page-title-main">Novobiocin</span> Chemical compound

Novobiocin, also known as albamycin or cathomycin, is an aminocoumarin antibiotic that is produced by the actinomycete Streptomyces niveus, which has recently been identified as a subjective synonym for S. spheroides a member of the class Actinomycetia. Other aminocoumarin antibiotics include clorobiocin and coumermycin A1. Novobiocin was first reported in the mid-1950s.

<span class="mw-page-title-main">Cyanidin</span> Anthocyanidin pigment in flowering plant petals and fruits

Cyanidin is a natural organic compound. It is a particular type of anthocyanidin. It is a pigment found in many red berries including grapes, bilberry, blackberry, blueberry, cherry, chokeberry, cranberry, elderberry, hawthorn, loganberry, açai berry and raspberry. It can also be found in other fruits such as apples and plums, and in red cabbage and red onion. It has a characteristic reddish-purple color, though this can change with pH; solutions of the compound are red at pH < 3, violet at pH 7-8, and blue at pH > 11. In certain fruits, the highest concentrations of cyanidin are found in the seeds and skin. Cyanidin has been found to be a potent sirtuin 6 (SIRT6) activator.

<span class="mw-page-title-main">Homogentisic acid</span> Chemical compound

Homogentisic acid is a phenolic acid usually found in Arbutus unedo (strawberry-tree) honey. It is also present in the bacterial plant pathogen Xanthomonas campestris pv. phaseoli as well as in the yeast Yarrowia lipolytica where it is associated with the production of brown pigments. It is oxidatively dimerised to form hipposudoric acid, one of the main constituents of the 'blood sweat' of hippopotamuses.

<span class="mw-page-title-main">4-Hydroxyphenylpyruvate dioxygenase</span> Fe(II)-containing non-heme oxygenase

4-Hydroxyphenylpyruvate dioxygenase (HPPD), also known as α-ketoisocaproate dioxygenase, is an Fe(II)-containing non-heme oxygenase that catalyzes the second reaction in the catabolism of tyrosine - the conversion of 4-hydroxyphenylpyruvate into homogentisate. HPPD also catalyzes the conversion of phenylpyruvate to 2-hydroxyphenylacetate and the conversion of α-ketoisocaproate to β-hydroxy β-methylbutyrate. HPPD is an enzyme that is found in nearly all aerobic forms of life.

<span class="mw-page-title-main">Rosmarinic acid</span> Chemical compound found in a variety of plants

Rosmarinic acid, named after rosemary, is a polyphenol constituent of many culinary herbs, including rosemary, perilla, sage, mint, and basil.

<span class="mw-page-title-main">Amino acid synthesis</span> The set of biochemical processes by which amino acids are produced

Amino acid synthesis is the set of biochemical processes by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. For example, humans can synthesize 11 of the 20 standard amino acids. These 11 are called the non-essential amino acids).

<span class="mw-page-title-main">Aromatic amino acid</span> Amino acid having an aromatic ring

An aromatic amino acid is an amino acid that includes an aromatic ring.

<span class="mw-page-title-main">Homogentisate 1,2-dioxygenase</span> Enzyme

Homogentisate 1,2-dioxygenase (homogentisic acid oxidase, homogentisate oxidase, homogentisicase) is an enzyme which catalyzes the conversion of homogentisate to 4-maleylacetoacetate. Homogentisate 1,2-dioxygenase or HGD is involved in the catabolism of aromatic rings, more specifically in the breakdown of the amino acids tyrosine and phenylalanine. HGD appears in the metabolic pathway of tyrosine and phenylalanine degradation once the molecule homogentisate is produced. Homogentisate reacts with HGD to produce maleylacetoacetate, which then is further used in the metabolic pathway. HGD requires the use of Fe2+ and O2 in order to cleave the aromatic ring of homogentisate.

<span class="mw-page-title-main">Dihydroxyphenylglycine</span> Chemical compound

(S)-3,5-Dihydroxyphenylglycine or DHPG is a potent agonist of group I metabotropic glutamate receptors (mGluRs) mGluR1 and mGluR5.

<span class="mw-page-title-main">Prephenate dehydrogenase</span> Class of enzymes

Prephenate dehydrogenase is an enzyme found in the shikimate pathway, and helps catalyze the reaction from prephenate to tyrosine.

In enzymology, a 4-hydroxymandelate synthase (EC 1.13.11.46) is an enzyme that catalyzes the chemical reaction

In enzymology, glutamate-prephenate aminotransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Shikimate pathway</span> Biosynthetic Pathway

The shikimate pathway is a seven-step metabolic pathway used by bacteria, archaea, fungi, algae, some protozoans, and plants for the biosynthesis of folates and aromatic amino acids. This pathway is not found in animal cells.

<span class="mw-page-title-main">Vancosamine</span> Chemical compound

Vancosamines are aminosugars that are a part of vancomycin and other molecules within the vancomycin family of antibiotics. Vancosamine synthesis is encoded by the vancomycin (vps) biosynthetic cluster. Epivancosamine, a closely related aminosugar, is encoded by the chloroeremomycin (cep) biosynthetic cluster.

<span class="mw-page-title-main">Chloroeremomycin</span> Chemical compound

Chloroeremomycin is a member of the glycopeptide family of antibiotics, such as vancomycin. The molecule is a non-ribosomal polypeptide that has been glycosylated. It is composed of seven amino acids and three saccharide units. Although chloroeremomycin has never been in clinical phases, oritavancin, a semi-synthetic derivative of chloroeremomycin, has been investigated.

References

  1. Yim, G., Thaker, M. N., Koteva, K., Wright, G. "Glycopeptide antibiotic biosynthesis." The Journal of Antibiotics, 2014, 67, 31-41.
  2. Choroba, O. W., Williams, D. H., Spencer, J. B. "Biosynthesis of the Vancomycin Group of Antibiotics: Involvement of an Unusual Dioxygenase in the Pathway to (S)-4-Hydroxyphenylglycine." J. Am. Chem. Soc.2000, 122, 5389-5390.
  3. Li, T.-L., Choroba, O. W., Charles, E. H., Sandercock, A. M., Williams, D. H., Spencer, J. B. "Characterisation of a hydroxymandelate oxidase involved in the biosynthesis of two unusual amino acids occurring in the vancomycin group of antibiotics." Chem. Commun.,2001, 1752-1753.
  4. Hubbard, B. K., Thomas, M. G., Walsh, C. T. "Biosynthesis of L-p-hydroxyphenylglycine, a non-proteogenic amino acid constituent of peptide antibiotics." Chemistry & Biology, 2000, 7 (12), 931-942.
  5. Kastner, S., Müller, S., Natesan, L., König, G. M., Guthke, R., Nett, M. "4-Hydroxyphenylglycine biosynthesis in Herpetosiphon aurantiacus: a case of gene duplication and catalytic divergence." Arch. Microbiol.2012, 194, 557-566.