PDBsum entry 1phm

Go to PDB code: 
protein ligands metals links
Monooxygenase PDB id
Protein chain
305 a.a. *
GOL ×4
_CU ×3
Waters ×226
* Residue conservation analysis
PDB id:
Name: Monooxygenase
Title: Peptidylglycine alpha-hydroxylating monooxygenase (phm) from
Structure: Peptidylglycine alpha-hydroxylating monooxygenase chain: a. Synonym: peptidylglycine monooxygenase, peptidylglycine 2- hydroxylase, phm. Engineered: yes. Other_details: two bound coppers
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Cell_line: dg44. Organ: pituitary. Organelle: secretory granule. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: dg44.
1.90Å     R-factor:   0.196     R-free:   0.261
Authors: S.T.Prigge,L.M.Amzel
Key ref:
S.T.Prigge et al. (1997). Amidation of bioactive peptides: the structure of peptidylglycine alpha-hydroxylating monooxygenase. Science, 278, 1300-1305. PubMed id: 9360928 DOI: 10.1126/science.278.5341.1300
10-Oct-97     Release date:   11-Nov-98    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P14925  (AMD_RAT) -  Peptidyl-glycine alpha-amidating monooxygenase
976 a.a.
305 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     oxidation-reduction process   2 terms 
  Biochemical function     catalytic activity     5 terms  


DOI no: 10.1126/science.278.5341.1300 Science 278:1300-1305 (1997)
PubMed id: 9360928  
Amidation of bioactive peptides: the structure of peptidylglycine alpha-hydroxylating monooxygenase.
S.T.Prigge, A.S.Kolhekar, B.A.Eipper, R.E.Mains, L.M.Amzel.
Many neuropeptides and peptide hormones require amidation at the carboxyl terminus for activity. Peptidylglycine alpha-amidating monooxygenase (PAM) catalyzes the amidation of these diverse physiological regulators. The amino-terminal domain of the bifunctional PAM protein is a peptidylglycine alpha-hydroxylating monooxygenase (PHM) with two coppers that cycle through cupric and cuprous oxidation states. The anomalous signal of the endogenous coppers was used to determine the structure of the catalytic core of oxidized rat PHM with and without bound peptide substrate. These structures strongly suggest that the PHM reaction proceeds via activation of substrate by a copper-bound oxygen species. The mechanistic and structural insight gained from the PHM structures can be directly extended to dopamine beta-monooxygenase.
  Selected figure(s)  
Figure 1.
Fig. 1. Reaction catalyzed by bifunctional PAM. The PHM domain catalyzes the oxygen- and ascorbate-dependent hydroxylation of peptidylglycine, forming the -hydroxyglycine intermediate. The PAL domain cleaves the intermediate and releases amidated peptide and glyoxylate. Colored atoms indicate that molecular oxygen is incorporated into -hydroxyglycine (26), and that the product amide nitrogen is derived from the substrate glycine (3).
Figure 2.
Fig. 2. A representation of the PHMcc fold. The backbone is shown in gray with the coppers represented by green spheres. Strands are numbered arrows and the cylinder is a 3[10] helix. Side chains of ligands to the two catalytic coppers (green spheres) are colored by atom type (carbon is gray, nitrogen is blue, sulfur is yellow). The dashed gray line indicates a six-residue loop (I176 to D181) not built into the final model. This figure was made with the program Setor (50).
  The above figures are reprinted by permission from the AAAs: Science (1997, 278, 1300-1305) copyright 1997.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21298193 F.G.Mutti, M.Gullotti, L.Casella, L.Santagostini, R.Pagliarin, K.K.Andersson, M.F.Iozzi, and G.Zoppellaro (2011).
A new chiral, poly-imidazole N8-ligand and the related di- and tri-copper(II) complexes: synthesis, theoretical modelling, spectroscopic properties, and biomimetic stereoselective oxidations.
  Dalton Trans, 40, 5436-5457.  
21069401 G.S.Siluvai, M.Nakano, M.Mayfield, and N.J.Blackburn (2011).
The essential role of the Cu(II) state of Sco in the maturation of the Cu(A) center of cytochrome oxidase: evidence from H135Met and H135SeM variants of the Bacillus subtilis Sco.
  J Biol Inorg Chem, 16, 285-297.  
19193193 B.Wan, X.R.Wang, Y.B.Zhou, X.Zhang, K.Huo, and Z.G.Han (2010).
C12ORF39, a novel secreted protein with a typical amidation processing signal.
  Biosci Rep, 30, 1.  
20544364 C.R.Hess, J.P.Klinman, and N.J.Blackburn (2010).
The copper centers of tyramine β-monooxygenase and its catalytic-site methionine variants: an X-ray absorption study.
  J Biol Inorg Chem, 15, 1195-1207.  
20648645 D.Bousquet-Moore, R.E.Mains, and B.A.Eipper (2010).
Peptidylgycine alpha-amidating monooxygenase and copper: a gene-nutrient interaction critical to nervous system function.
  J Neurosci Res, 88, 2535-2545.  
20074584 E.A.Nillni (2010).
Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs.
  Front Neuroendocrinol, 31, 134-156.  
20943906 E.D.Gaier, R.M.Rodriguiz, X.M.Ma, S.Sivaramakrishnan, D.Bousquet-Moore, W.C.Wetsel, B.A.Eipper, and R.E.Mains (2010).
Haploinsufficiency in peptidylglycine alpha-amidating monooxygenase leads to altered synaptic transmission in the amygdala and impaired emotional responses.
  J Neurosci, 30, 13656-13669.  
20715282 E.Langella, S.Pierre, W.Ghattas, M.Giorgi, M.Réglier, M.Saviano, L.Esposito, and R.Hardré (2010).
Probing the peptidylglycine alpha-hydroxylating monooxygenase active site with novel 4-phenyl-3-butenoic acid based inhibitors.
  ChemMedChem, 5, 1568-1576.  
19604476 E.E.Chufán, M.De, B.A.Eipper, R.E.Mains, and L.M.Amzel (2009).
Amidation of bioactive peptides: the structure of the lyase domain of the amidating enzyme.
  Structure, 17, 965-973.
PDB codes: 3fvz 3fw0
19216527 H.R.Lucas, L.Li, A.A.Sarjeant, M.A.Vance, E.I.Solomon, and K.D.Karlin (2009).
Toluene and ethylbenzene aliphatic C-H bond oxidations initiated by a dicopper(II)-mu-1,2-peroxo complex.
  J Am Chem Soc, 131, 3230-3245.  
19569683 N.R.McIntyre, E.W.Lowe, and D.J.Merkler (2009).
Imino-oxy acetic acid dealkylation as evidence for an inner-sphere alcohol intermediate in the reaction catalyzed by peptidylglycine alpha-hydroxylating monooxygenase.
  J Am Chem Soc, 131, 10308-10319.  
  18818385 S.D.Sharma, G.Raghuraman, M.S.Lee, N.R.Prabhakar, and G.K.Kumar (2009).
Intermittent hypoxia activates peptidylglycine alpha-amidating monooxygenase in rat brain stem via reactive oxygen species-mediated proteolytic processing.
  J Appl Physiol, 106, 12-19.  
18830721 S.M.Berry, J.R.Mayers, and N.A.Zehm (2009).
Models of noncoupled dinuclear copper centers in azurin.
  J Biol Inorg Chem, 14, 143-149.  
18779326 A.Romero, I.Cakir, C.A.Vaslet, R.C.Stuart, O.Lansari, H.A.Lucero, and E.A.Nillni (2008).
Role of a pro-sequence in the secretory pathway of prothyrotropin-releasing hormone.
  J Biol Chem, 283, 31438-31448.  
18952446 D.J.Merkler, A.S.Asser, L.E.Baumgart, N.Carballo, S.E.Carpenter, G.H.Chew, C.C.Cosner, J.Dusi, L.C.Galloway, A.B.Lowe, E.W.Lowe, L.King, R.D.Kendig, P.C.Kline, R.Malka, K.A.Merkler, N.R.McIntyre, M.Romero, B.J.Wilcox, and T.C.Owen (2008).
Substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine alpha-hydroxylating monooxygenase (PHM).
  Bioorg Med Chem, 16, 10061-10074.  
18399242 T.Fujii, S.Yamaguchi, S.Hirota, and H.Masuda (2008).
H-atom abstraction reaction for organic substrates via mononuclear copper(II)-superoxo species as a model for DbetaM and PHM.
  Dalton Trans, (), 164-170.  
17013614 D.F.Raffa, G.A.Rickard, and A.Rauk (2007).
Ab initio modelling of the structure and redox behaviour of copper(I) bound to a His-His model peptide: relevance to the beta-amyloid peptide of Alzheimer's disease.
  J Biol Inorg Chem, 12, 147-164.  
17472331 E.I.Solomon, R.Sarangi, J.S.Woertink, A.J.Augustine, J.Yoon, and S.Ghosh (2007).
O2 and N2O activation by Bi-, Tri-, and tetranuclear Cu clusters in biology.
  Acc Chem Res, 40, 581-591.  
17011183 A.C.Rosenzweig, and M.H.Sazinsky (2006).
Structural insights into dioxygen-activating copper enzymes.
  Curr Opin Struct Biol, 16, 729-735.  
16344970 B.F.Gherman, D.E.Heppner, W.B.Tolman, and C.J.Cramer (2006).
Models for dioxygen activation by the CuB site of dopamine beta-monooxygenase and peptidylglycine alpha-hydroxylating monooxygenase.
  J Biol Inorg Chem, 11, 197-205.  
17019721 B.F.Gherman, W.B.Tolman, and C.J.Cramer (2006).
Characterization of the structure and reactivity of monocopper-oxygen complexes supported by beta-diketiminate and anilido-imine ligands.
  J Comput Chem, 27, 1950-1961.  
17033702 D.E.Heppner, B.F.Gherman, W.B.Tolman, and C.J.Cramer (2006).
Can an ancillary ligand lead to a thermodynamically stable end-on 1 : 1 Cu-O2 adduct supported by a beta-diketiminate ligand?
  Dalton Trans, (), 4773-4782.  
16791638 I.Bento, M.A.Carrondo, and P.F.Lindley (2006).
Reduction of dioxygen by enzymes containing copper.
  J Biol Inorg Chem, 11, 539-547.  
16522125 N.W.Aboelella, B.F.Gherman, L.M.Hill, J.T.York, N.Holm, V.G.Young, C.J.Cramer, and W.B.Tolman (2006).
Effects of thioether substituents on the O2 reactivity of beta-diketiminate-Cu(I) complexes: probing the role of the methionine ligand in copper monooxygenases.
  J Am Chem Soc, 128, 3445-3458.  
17057866 T.Fujii, S.Yamaguchi, Y.Funahashi, T.Ozawa, T.Tosha, T.Kitagawa, and H.Masuda (2006).
Mononuclear copper(II)-hydroperoxo complex derived from reaction of copper(I) complex with dioxygen as a model of DbetaM and PHM.
  Chem Commun (Camb), (), 4428-4430.  
15691328 A.Asada, H.Orii, K.Watanabe, and M.Tsubaki (2005).
Planarian peptidylglycine-hydroxylating monooxygenase, a neuropeptide processing enzyme, colocalizes with cytochrome b561 along the central nervous system.
  FEBS J, 272, 942-955.  
15811799 A.Decker, and E.I.Solomon (2005).
Dioxygen activation by copper, heme and non-heme iron enzymes: comparison of electronic structures and reactivities.
  Curr Opin Chem Biol, 9, 152-163.  
16187071 C.R.Kinsinger, B.F.Gherman, L.Gagliardi, and C.J.Cramer (2005).
How useful are vibrational frequencies of isotopomeric O2 fragments for assessing local symmetry? Some simple systems and the vexing case of a galactose oxidase model.
  J Biol Inorg Chem, 10, 778-789.  
16234916 R.L.Lieberman, and A.C.Rosenzweig (2005).
The quest for the particulate methane monooxygenase active site.
  Dalton Trans, (), 3390-3396.  
16100265 X.Siebert, B.A.Eipper, R.E.Mains, S.T.Prigge, N.J.Blackburn, and L.M.Amzel (2005).
The catalytic copper of peptidylglycine alpha-hydroxylating monooxygenase also plays a critical structural role.
  Biophys J, 89, 3312-3319.
PDB codes: 1yi9 1yip 1yjk 1yjl
16170781 Y.C.Chen, and J.K.Hwang (2005).
Prediction of disulfide connectivity from protein sequences.
  Proteins, 61, 507-512.  
15340147 P.Chen, and E.I.Solomon (2004).
O2 activation by binuclear Cu sites: noncoupled versus exchange coupled reaction mechanisms.
  Proc Natl Acad Sci U S A, 101, 13105-13110.  
15574324 S.D.Benson, J.K.Bamford, D.H.Bamford, and R.M.Burnett (2004).
Does common architecture reveal a viral lineage spanning all three domains of life?
  Mol Cell, 16, 673-685.  
15597398 S.Dove (2004).
Picolinic acids as inhibitors of dopamine beta-monooxygenase: QSAR and putative binding site.
  Arch Pharm (Weinheim), 337, 645-653.  
12455001 B.Hollins, D.Hardin, A.A.Gimelbrant, and T.S.McClintock (2003).
Olfactory-enriched transcripts are cell-specific markers in the lobster olfactory organ.
  J Comp Neurol, 455, 125-138.  
11857564 C.H.Kim, C.P.Zabetian, J.F.Cubells, S.Cho, I.Biaggioni, B.M.Cohen, D.Robertson, K.S.Kim, and D.Robertson (2002).
Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency.
  Am J Med Genet, 108, 140-147.  
11863465 D.E.Benson, A.E.Haddy, and H.W.Hellinga (2002).
Converting a maltose receptor into a nascent binuclear copper oxygenase by computational design.
  Biochemistry, 41, 3262-3269.  
12404359 E.I.Solomon, P.Chen, M.Metz, S.K.Lee, and A.E.Palmer (2001).
Oxygen Binding, Activation, and Reduction to Water by Copper Proteins.
  Angew Chem Int Ed Engl, 40, 4570-4590.  
11389601 S.Jaron, and N.J.Blackburn (2001).
Characterization of a half-apo derivative of peptidylglycine monooxygenase. Insight into the reactivity of each active site copper.
  Biochemistry, 40, 6867-6875.  
10891082 W.J.Driscoll, S.König, H.M.Fales, L.K.Pannell, B.A.Eipper, and G.P.Mueller (2000).
Peptidylglycine-alpha-hydroxylating monooxygenase generates two hydroxylated products from its mechanism-based suicide substrate, 4-phenyl-3-butenoic acid.
  Biochemistry, 39, 8007-8016.  
10079066 B.J.Wilcox, K.J.Ritenour-Rodgers, A.S.Asser, L.E.Baumgart, M.A.Baumgart, D.L.Boger, J.L.DeBlassio, M.A.deLong, U.Glufke, M.E.Henz, L.King, K.A.Merkler, J.E.Patterson, J.J.Robleski, J.C.Vederas, and D.J.Merkler (1999).
N-acylglycine amidation: implications for the biosynthesis of fatty acid primary amides.
  Biochemistry, 38, 3235-3245.  
10508581 D.N.Shelton, E.Chang, P.S.Whittier, D.Choi, and W.D.Funk (1999).
Microarray analysis of replicative senescence.
  Curr Biol, 9, 939-945.  
10226046 H.C.Liang, M.Dahan, and K.D.Karlin (1999).
Dioxygen-activating bio-inorganic model complexes.
  Curr Opin Chem Biol, 3, 168-175.  
10080383 L.H.Lazarus, S.D.Bryant, P.S.Cooper, and S.Salvadori (1999).
What peptides these deltorphins be.
  Prog Neurobiol, 57, 377-420.  
10226045 M.A.McGuirl, and D.M.Dooley (1999).
Copper-containing oxidases.
  Curr Opin Chem Biol, 3, 138-144.  
10353829 M.Ralle, M.L.Verkhovskaya, J.E.Morgan, M.I.Verkhovsky, M.Wikström, and N.J.Blackburn (1999).
Coordination of CuB in reduced and CO-liganded states of cytochrome bo3 from Escherichia coli. Is chloride ion a cofactor?
  Biochemistry, 38, 7185-7194.  
10353818 N.J.Blackburn, M.Ralle, E.Gomez, M.G.Hill, A.Pastuszyn, D.Sanders, and J.A.Fee (1999).
Selenomethionine-substituted Thermus thermophilus cytochrome ba3: characterization of the CuA site by Se and Cu K-EXAFS.
  Biochemistry, 38, 7075-7084.  
10571999 S.Hirota, T.Iwamoto, K.Tanizawa, O.Adachi, and O.Yamauchi (1999).
Spectroscopic characterization of carbon monoxide complexes generated for copper/topa quinone-containing amine oxidases.
  Biochemistry, 38, 14256-14263.  
10563791 S.Jaron, and N.J.Blackburn (1999).
Does superoxide channel between the copper centers in peptidylglycine monooxygenase? A new mechanism based on carbon monoxide reactivity.
  Biochemistry, 38, 15086-15096.  
9667936 B.G.Malmström, and J.Leckner (1998).
The chemical biology of copper.
  Curr Opin Chem Biol, 2, 286-292.  
9667917 D.F.Steiner (1998).
The proprotein convertases.
  Curr Opin Chem Biol, 2, 31-39.  
9914255 U.Ermler, W.Grabarse, S.Shima, M.Goubeaud, and R.K.Thauer (1998).
Active sites of transition-metal enzymes with a focus on nickel.
  Curr Opin Struct Biol, 8, 749-758.  
9609721 W.A.Francisco, D.J.Merkler, N.J.Blackburn, and J.P.Klinman (1998).
Kinetic mechanism and intrinsic isotope effects for the peptidylglycine alpha-amidating enzyme reaction.
  Biochemistry, 37, 8244-8252.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.