[12] X.H. Yin, T. O'Hare, S.J. Gould, T.M. Zabriskie, Identification and cloning of genes encoding viomycin biosynthesis from Streptomyces
vinaceus and evidence for involvement of a rare oxygenase, Gene, 312 (2003) 215-224.
[13] C.C. Lawrence, W.J. Sobey, R.A. Field, J.E. Baldwin, C.J. Schofield, Purification and initial characterization of proline 4-hydroxylase from
Streptomyces griseoviridus P8648: A 2-oxoacid, ferrous-dependent dioxygenase involved in etamycin biosynthesis, Biochem J, 313 (1996) 185-
191.
[14] J.E. Baldwin, R.A. Field, C.C. Lawrence, V. Lee, J.K. Robinson, C.J. Schofield, Substrate-Specificity of Proline 4-Hydroxylase - Chemical and
Enzymatic-Synthesis of 2s,3r,4s-Epoxyproline, Tetrahedron Lett, 35 (1994) 4649-4652.
[15] H. Mori, T. Shibasaki, K. Yano, A. Ozaki, Purification and cloning of a proline 3-hydroxylase, a novel enzyme which hydroxylates free L-proline
to cis-3-hydroxy-L-proline, J Bacteriol, 179 (1997) 5677-5683.
[16] T. Shibasaki, H. Mori, A. Ozaki, Development of the regio- and stereospecific proline hydroxylases and their application, J Syn Org Chem Jpn,
57 (1999) 523-531.
[17] T. Shibasaki, H. Mori, S. Chiba, A. Ozaki, Microbial proline 4-hydroxylase screening and feme cloning, Appl Environ Microb, 65 (1999) 4028-
4031.
[18] T. Shibasaki, H. Mori, A. Ozaki, Enzymatic production of trans-4-hydroxy-L-proline by regio- and stereospecific hydroxylation of L-proline,
Biosci Biotech Bioch, 64 (2000) 746-750.
[19] T. Shibasaki, S. Hashimoto, H. Mori, A. Ozaki, Construction of a novel hydroxyproline-producing recombinant Escherichia coli by introducing a
proline 4-hydroxylase gene, J Biosci Bioeng, 90 (2000) 522-525.
[20] T. Shibasaki, H. Mori, A. Ozaki, Cloning of an isozyme of proline 3-hydroxylase and its purification from recombinant Escherichia coli,
Biotechnol Lett, 22 (2000) 1967-1973.
[21] R. Hara, K. Kino, Characterization of novel 2-oxoglutarate dependent dioxygenases converting L-proline to cis-4-hydroxy-L-proline, Biochem
Bioph Res Co, 379 (2009) 882-886.
[22] C. Klein, W. Huttel, A Simple Procedure for Selective Hydroxylation of L-Proline and L-Pipecolic Acid with Recombinantly Expressed Proline
Hydroxylases, Adv Synth Catal, 353 (2011) 1375-1383.
[23] C. Klein, W. Huttel, Tertiary alcohol preferred: Hydroxylation of trans-3-methyl-L-proline with proline hydroxylases, Beilstein J Org Chem, 7
(2011) 1643-1647.
[24] F. Falcioni, L.M. Blank, O. Frick, A. Karau, B. Buhler, A. Schmid, Proline Availability Regulates Proline-4-Hydroxylase Synthesis and Substrate
Uptake in Proline-Hydroxylating Recombinant Escherichia coli, Appl Environ Microb, 79 (2013) 3091-3100.
[25] W. Huttel, Biocatalytic Production of Chemical Building Blocks in Technical Scale with alpha-Ketoglutarate-Dependent Dioxygenases, Chem-
Ing-Tech, 85 (2013) 809-817.
[26] R. Hara, N. Uchiumi, N. Okamoto, K. Kino, Regio- and stereoselective oxygenation of proline derivatives by using microbial 2-oxoglutarate-
dependent dioxygenases, Biosci Biotech Bioch, 78 (2014) 1384-1388.
[27] K. Koketsu, Y. Shomura, K. Moriwaki, M. Hayashi, S. Mitsuhashi, R. Hara, K. Kino, Y. Higuchi, Refined Regio- and Stereoselective
Hydroxylation of L-Pipecolic Acid by Protein Engineering of L-Proline cis-4-Hydroxylase Based on the X-ray Crystal Structure, Acs Synth Biol, 4
(2015) 383-392.
[28] I.J. Clifton, L.C. Hsueh, J.E. Baldwin, K. Harlos, C.J. Schofield, Structure of proline 3-hydroxylase - Evolution of the family of 2-oxoglutarate
dependent oxygenases, Eur J Biochem, 268 (2001) 6625-6636.
[29] W. Aik, M.A. McDonough, A. Thalhammer, R. Chowdhury, C.J. Schofield, Role of the jelly-roll fold in substrate binding by 2-oxoglutarate
oxygenases, Curr Opin Struct Biol, 22 (2012) 691-700.
[30] W.S. Aik, R. Chowdhury, I.J. Clifton, R.J. Hopkinson, T. Leissing, M.A. McDonough, R. Nowak, C.J. Schofield, L.J. Walport, Introduction to
structural studies on 2-oxoglutarate-dependent oxygenases and related enzymes, RSC Metallobiology2015, pp. 59-94.
[31] J.E. Baldwin, R.A. Field, C.C. Lawrence, K.D. Merritt, C.J. Schofield, Proline 4-Hydroxylase - Stereochemical Course of the Reaction,
Tetrahedron Lett, 34 (1993) 7489-7492.
[32] T. Shibasaki, W. Sakurai, A. Hasegawa, Y. Uosaki, H. Mori, M. Yoshida, A. Ozaki, Substrate selectivities of proline hydroxylases, Tetrahedron
Lett, 40 (1999) 5227-5230.
[33] H. Mori, T. Shibasaki, Y. Uozaki, K. Ochiai, A. Ozaki, Detection of novel proline 3-hydroxylase activities in Streptomyces and Bacillus spp by
regio- and stereospecific hydroxylation of L-proline, Appl Environ Microb, 62 (1996) 1903-1907.
[34] R.F. Li, A. Stapon, J.T. Blanchfield, C.A. Townsend, Three unusual reactions mediate carbapenem and carbapenam biosynthesis, J Am Chem
Soc, 122 (2000) 9296-9297.
[35] M.C. Sleeman, C.J. Schofield, Carboxymethylproline synthase (CarB), an unusual carbon-carbon bond-forming enzyme of the crotonase
superfamily involved in carbapenem biosynthesis, J Biol Chem, 279 (2004) 6730-6736.
[36] M.C. Sleeman, J.L. Sorensen, E.T. Batchelar, M.A. McDonough, C.J. Schofield, Structural and mechanistic studies on carboxymethylproline
synthase (CarB), a unique member of the crotonase superfamily catalyzing the first step in carbapenem biosynthesis, J Biol Chem, 280 (2005)
34956-34965.
[37] C. Loenarz, J. Mecinovic, R. Chowdhury, L.A. McNeill, E. Flashman, C.J. Schofield, Evidence for a Stereoelectronic Effect in Human Oxygen
Sensing, Angew Chem Int Edit, 48 (2009) 1784-1787.
[38] A.M. Rydzik, I.K. Leung, G.T. Kochan, A. Thalhammer, U. Oppermann, T.D. Claridge, C.J. Schofield, Development and application of a
fluoride-detection-based fluorescence assay for γ-butyrobetaine hydroxylase, Chembiochem, 13 (2012) 1559-1563.
[39] A.M. Rydzik, R. Chowdhury, G.T. Kochan, S.T. Williams, M.A. McDonough, A. Kawamura, C.J. Schofield, Modulating carnitine levels by
targeting its biosynthesis - selective inhibition of gamma-butyrobetaine hydroxylase, Chem Sci, 5 (2014) 1765-1771.
Fig. 1. (a) Products of proline hydroxylase (PH) reactions using the natural substrate (L-proline, 1) [(2S,3S)-cis-3-hydroxy-L-proline (2), (2S,4S)-
cis-4-hydroxy-L-proline (3), and (2S,4R)-trans-4-hydroxy-L-proline (4)], and (b) the stoichiometry of the proline-hydroxylase reactions.
Fig. 2. Products generated by proline hydroxylases using substrate analogues with different ring sizes (4-, 6- and 7-membered rings). In this and
subsequent schemes all PH catalysed reactions are coupled to the oxidation of 2OG /O2 to succinate/CO2. Note the precise structures of some products are
unassigned. See Supplementary Information for details of incubations, structure assignments and (approximate) yields (Table S7).
Fig. 3. Products generated by proline hydroxylases using N-methylated substrates analogues: the products appear analogous to those produced
with the unmethylated analogues (Fig. 1). See Supplementary Information for details of incubations, structure assignments, and (approximate) yields
(Table S7).
5