Abstract
The synthesis and chemistry of the lesser-known phosphoamino acids, O-phosphohydroxylysine, O-phosphohydroxyproline, N 1-phosphotryptophan and S-phosphocysteine are described in detail. In addition, where anything at all is known, the biological synthesis, occurrence and functions of these phosphoamino acids are described. Of these phosphoamino acids, only N 1-phosphotryptophan has not been reported to occur in proteins; however, apart from the roles of S-phosphocysteine in the sugar transporter component (EII) and in catalysis by protein phosphotyrosine phosphatase, little is currently known about the biological roles of the phosphoamino acids when they occur as post-translational modifications.
Similar content being viewed by others
Notes
Note, the use of D/L by Hubálek et al. (2002) to describe the mixture of configurations at C5 of the lysine residue is incorrect. Either allo/threo or, better, R/S should be used (allo = S, threo = R).
References
Adams E, Frank L (1980) Metabolism of proline and the hydroxyprolines. Ann Rev Biochem 49:1005–1061
Åkerfeldt S (1960) Cysteamine S-phosphoric acid. Acta Chem Scand 14:1980–1984
Åkerfeldt S (1961) Further studies on S-substituted phosphorothioic acids. Mixed lithium sodium salts of S-(1-carboxyethyl) phosphorothioic acid and S-(2-carboxyethyl) phosphorothioic acid. Acta Chem Scand 15:575–582
Åkerfeldt S (1963) Further studies on S-substituted phosphorothioic acids. Rates of hydrolysis and dissociation constants. Acta Chem Scand 15:319–328
Astrup T, Carlström G, Stage A (1951) Free amino acids in mammalian tissue. Acta Physiol Scand 24:202–211
Attwood PV, Wieland T (2015) Nucleoside diphosphate kinase as protein histidine kinaseNaunyn-Schmiedeberg’s Arch. Pharmacol 388:153–160
Attwood PV, Piggott MJ, Besant PG (2007) Focus on phosphohistidine. Amino Acids 32:145–155
Attwood PV, Piggott MJ, Besant PG (2011) Focus on phosphoaspartate and phosphoglutamate. Amino Acids 40:1035–1051
Bertran-Vicente J, Penkert M, Nieto-Garcia O, Jeckelmann J-M, Schmieder P, Krause E, Hackenberger CPR (2017) Chemoselective synthesis and analysis of naturally occurring phosphorylated cysteine peptides. Nat Commun 7:12703. doi:10.1038/ncomms12703
Besant PG, Attwood PV, Piggott MJ (2009) Focus on phosphoarginine and phospholysine. Curr Protein Pept Sci 10:536–550
Binkley F (1952) Preparation and properties of S-phosphocysteine. J Biol Chem 195:283–285
Brandão TA, Hengge AC, Johnson SJ (2010) Insights into the reaction of protein-tyrosine phosphatase 1B: crystal structures for transition state analogs of both catalytic steps. J Biol Chem 285:15874–15883
Buchowiecka AK (2014) Puzzling over protein cysteine phosphorylation—assessment of proteomic tools for S-phosphorylation profiling. Analyst 139:4118–4123
Calam DH, Waley SG (1964) Amino acids and related compounds in the lens. Biochem J 93:526–532
Calogero S, Lanari D, Orrù M, Piermatti O, Pizzo F, Vaccaro L (2011) Supported l-proline on zirconium phosphates methyl and/or phenyl phosphonates as heterogeneous organocatalysts for direct asymmetric aldol addition. J Catal 282:112–119
Chang AY (1977) Guanisine triphosphate:5-hydroxylysine phosphotransferase in rat kidney cortex. Enzyme 22:230–234
Chen PR, Brugarolas P, He C (2011) Redox signaling in human pathogens antioxid. Redox Signal 14:1107–1118
Chooi KP, Galan SRG, Raj R, McCullagh J, Mohammed S, Jones LH, Davis B (2014) Synthetic phosphorylation of p38α recapitulates protein kinase activity. J Am Chem Soc 136:1698–1701
Davis JP, Zhou MM, Van Etten RL (1994) Kinetic and site-directed mutagenesis studies of the cysteine residues of bovine low molecular weight phosphotyrosyl protein phosphatase. J Biol Chem 269:8734–8740
Deshimaru S, Miyake Y, Ohmiya T, Tatsu Y, Endo Y, Yumoto N, Toraya T (2002) Heterologous expression and catalytic properties of the C-terminal domain of starfish cdc25 dual-specificity phosphatase, a cell cycle regulator. J Biochem 131:705–712
Dorland L, Duran M, de Bree PK, Smith GR, Horvath A, Tibosch AS, Wadman SK (1990) Phosphohydroxylysininuria: a new inborn error of metabolism. Clin Chim Acta 18:221–226
Dreef-Tromp CM, Lefeber AWM, van der Marel GA, van Boom JH (1992) Synthesis and phosphorylating properties of hydroxamino acid phosphoramidites. Synthesis 12:1269–1272
Feramisco JR, Kemp BE, Krebs EG (1979) Phosphorylation of hydroxyproline in a synthetic peptide catalyzed by cyclic AMP-dependent protein kinase. J Biol Chem 254:6987–6990
Gemmecker G, Eberstadt M, Buhr A, Lanz R, Grdadolnik SG, Kessler H, Erni B (1997) Glucose transporter of Escherichia coli: NMR characterization of the phosphocysteine form of the IIB(Glc) domain and its binding interface with the IIA(Glc) subunit. Biochemistry 36:7408–7418
Gordon AH (1948) Occurrence of a phosphoester of a hydroxyamino-acid. Nature 162:778
Gordon AH (1949) An investigation of the intracellular fluid of calf embryo muscle. Biochem J 45:99–105
Grant ME (2007) From collagen chemistry towards cell therapy—a personal journey. Int J Exp Path 88:203–214
Guillaume HA, Perich JW, Johns RB, Tregear GW (1989a) Synthesis of N(1)-phosphorylated tryptophan derivatives. J Org Chem 54:1664–1668
Guillaume HA, Perich JW, Wade JD, Tregear GW, Johns RB (1989b) Synthesis of an N 1-phosphotryptophan-containing tripeptide: glutamyl-N 1-phosphotryptophanylleucine. J Org Chem 54:5731–5736
Hiles RA, Henderson LM (1972) Partial purification and properties of hydroxylysine kinse from rat liver. J Biol Chem 247:646–651
Hiles RA, Triebwasser KC, Henderson LM (1970) The degradation of hyroxyl-l-lysine in liver via its phosphate ester. Biochem Biophys Res Commun 41:662–668
Hiles RA, Willett CJ, Henderson LM (1972) Hydroxylysine metabolism in rats, mice and chickens. J Nutr 102:195–204
Hoffmann R, Reichert I, Wachs WO, Zeppezauer M, Kalbitzer HR (1994) 1H and 31P NMR spectroscopy of phosphorylated model peptides. Int J Pept Protein Res 44:193–198
Hoffmann R, Hoffmann T, Tholey A, Schulte AC, Kalbitzer HR (1997) Synthesis and NMR spectroscopy of peptides containing either phosphorylated or phosphonylated cis- or trans-4-hydroxyproline. J Peptide Res 49:163–173
Hubálek F, Edmondson DE, Pohl J (2002) Synthesis and characterization of a collagen model δ-O-phosphohydroxylysine-containing peptide. Anal Biochem 306:124–134
Inglis AS (1983) Single hydrolysis method for all amino acids, including cysteine and tryptophan. Meth Enzymol 91:26–36
Iwashita M, Makide K, Nonomura T, Misumi Y, Otani Y, Ishida M, Taguchi R, Tsujimoto M, Aoki J, Arai H, Ohwada T (2009) Synthesis and evaluation of lysophosphatidylserine analogues as inducers of mast cell degranulation. Potent activities of lysophosphatidylthreonine and its 2-deoxy derivative. J Med Chem 52:5837–5863
Kawashima H, Yamada Y (1972) Patent: Jpn. Kokai Tokkyo Koho JP 48018233(B4):19720307
Kivirikko KI, Pihlajaniemi T (1998) Collagen hydroxylases and the protein disulfide isomerase subunit of prolyl 4-hydroxylases. Adv Enzymol Relat Areas Mol Biol 72:325–398
Knott L, Bailey AJ (1998) Collagen cross-links in mineralizing tissues: a review of their chemistry, function, and clinical relevance. Bone 22:181–187
Knox JP (1995) The extracellular matrix in higher plants. 4. Developmentally regulated proteoglycans and glycoproteins of the plant cell surface. FASEB J 9:1004–1012
Krane SM (2008) The importance of proline residues in the structure, stability and susceptibility to proteolytic degradation of collagens. Amino Acids 35:703–710
Kühlberg A, Haid M, Metzger S (2010) Characterization of O-phosphohydroxyproline in rat α-crystallin A. J Biol Chem 280:31484–31490
Kulik W, Heerma W, Dorland L, de Bree PK, Duran M (1989) Fast atom bombardment tandem mass spectrometry of phosphohydroxylysine and related phosphohydroxy amino acids. Rapid Commun Mass Spect 3:76–78
McClure M, DeLucas LJ, Wilson L, Ray M, Rowe SM, Wu X, Dai Q, Hong JS, Sorscher EJ, Kappes JC, Barnes S (2012) ASMS Conference on Mass Spectrometry and Allied Topics, 2012, TP05 Poster 113, http://app.imswift.com/asms2012/sessions/asms_3385
McClure M, DeLucas LJ, Wilson L, Ray M, Rowe SM, Wu X, Dai Q, Hong JS, Sorscher EJ, Kappes JC, Barnes S (2014) Purification of CFTR for mass spectrometry analysis: identification of palmitoylation and other post-translational modifications. Protein Eng Des Sel 25:7–14
Meins M, Jenö P, Müller D, Richter WJ, Rosenbusch JP, Erni B (1993) Cysteine phosphorylation of the glucose transporter of Escherichia coli. J Biol Chem 268:11604–11609
Nakajima T, Volcani BE (1969) 3,4-Dihydroxyproline: a new amino acid in diatom cell walls. Science 164:1400–1401
Neumann H (1968) Substrate selectivity in the action of alkaline and acid phosphatases. J Biol Chem 243:4671–4676
Pandey AK, Naduthambi D, Thomas KM, Zondlo NJ (2013) J Am Chem Soc 135:4333–4363
Pannifer AD, Flint AJ, Tonks NK, Barford D (1998) Visualization of the cysteinyl-phosphate intermediate of a protein-tyrosine phosphatase by X-ray crystallography. J Biol Chem 273:10454–10462
Pas HH, Robillard GT (1988) S-phosphocysteine and phosphohistidine are intermediates in the phosphoenolpyruvate-dependent mannitol transport catalyzed by Escherichia coli EIIMtl. Biochemistry 27:5835–5839
Pas HH, Meyer GH, Kruizinga WH, Tamminga KS, van Weeghel RP, Robillard GT (1991) 31phospho-NMR demonstration of phosphocysteine as a catalytic intermediate on the Escherichia coli phosphotransferase system EIIMtl. J Biol Chem 266:6690–6692
Pearson RB, Floyd DM, Hunt JT, Lee VG, Kemp BE (1988) Hydroxyamino acid specificity of smooth muscle myosin light chain kinase. Arch Biochem Biophys 260:37–44
Piper JR, Rose LM, Johnston TP, Grenan M (1979) S-2, omega-Diaminoalkyl dihydrogen phosphorothioates as antiradiation agents. J Med Chem 22:631–639
Plimmer RHA (1941) Esters of phosphoric acid 4. Phosphoryl hydroxyamino-acids. Biochem J 35:461–469
Rowan FC, Richards M, Bibby RA, Thompson A, Bayliss R, Blagg J (2013) Insights into aurora-A kinase activation using unnatural amino acids incorporated by chemical modification. Chem Biol 8:2184–2191
Rudolph R (2007) Cdc25 phosphatases: structure, specificity, and mechanism. Biochemistry 46:3595–3604
Schulte MK, Whittemore ER, Koerner JF, Johnson RL (1992) Structure-function relationships for analogues of L-2-amino-4-phosphonobutanoic acid on the quisqualic acid-sensitive AP4 receptor of the rat hippocampus. Brain Res 582:291–298
Sprinson DB, Weliky I (1969) The conversion of ethanolamine to acetate in mammalian tissues. Biochem Biophys Res Commun 36:866–870
Sripada PK, Hosain F, Spencer RP, Clampitt KS (1982) Synthesis, radiotechnetium labeling and biodistribution of 4-Phosphoryl-L-Proline. Int J Nucl Med Biol 9:53–55
Stadtman TC (1994) Emerging awareness of the critical roles of S-phosphocysteine and selenophosphate in biological systems. BioFactors 4:181–185
Sun F, Ding Y, Ji Q, Liang Z, Deng X, Wong CC, Yi C, Zhang L, Xie S, Alvarez S, Hicks LM, Luo C, Jiang H, Lan L, He C (2012) Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance. Proc Natl Acad Sci USA 109:15461–15466
Tsai CH, Henderson LM (1974) Degradation of O-phosphohydroxylysine by rat liver. Purification of the phospho-lyase. J Biol Chem 249:5784–5789
Urushizaki Y, Seifter S (1985) Phosphorylation of hydroxylysine residues in collagen synthesised by cultured aortic smooth muscle cells. Proc Natl Acad Sci USA 82:3091–3095
Veiga-da-Cunha M, Hadi F, Balligand T, Stroobant V, Van Schaftingen E (2012) Molecular identification of hydroxylysine kinase and of ammoniophospholyases acting on 5-phosphohydroxy-l-lysine and phosphoethanolamine. J Biol Chem 287:7246–7255
Veiga-da-Cunha M, Vehoeven-Duif NM, de Koning TJ, Duran M, Dorland B, Van Schaftingen E (2013) Mutations in the AGXT2L2 gene cause phosphohydroxylysinuria. J Inherit Metab Dis 36:961–966
Wang ZU, Wang Y-S, Pai P-J, Russell WK, Russell DH, Wenshe RL (2012) A facile method to synthesize histones with posttranslational modification mimics. Biochemistry 51:5232–5234
Xiang Q, Edmonson DE (1997) Flavins and flavoproteins. In: Stevenson KJ, Massey V, Williams CH Jr (eds), University of Calgary Press, Calgary, pp 851–856
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical statement
This article does not contain any studies with human participants or animals performed by any of the authors.
Additional information
Handling Editor: J. D. Wade.
Rights and permissions
About this article
Cite this article
Piggott, M.J., Attwood, P.V. Focus on O-phosphohydroxylysine, O-phosphohydroxyproline, N 1-phosphotryptophan and S-phosphocysteine. Amino Acids 49, 1309–1323 (2017). https://doi.org/10.1007/s00726-017-2446-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-017-2446-x