PMID- 27014201
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20160325
LR  - 20200930
IS  - 1664-302X (Print)
IS  - 1664-302X (Electronic)
IS  - 1664-302X (Linking)
VI  - 7
DP  - 2016
TI  - New Concept of the Biosynthesis of 4-Alkyl-L-Proline Precursors of Lincomycin, 
      Hormaomycin, and Pyrrolobenzodiazepines: Could a gamma-Glutamyltransferase Cleave the 
      C-C Bond?
PG  - 276
LID - 10.3389/fmicb.2016.00276 [doi]
LID - 276
AB  - Structurally different and functionally diverse natural compounds - antitumour 
      agents pyrrolo[1,4]benzodiazepines, bacterial hormone hormaomycin, and 
      lincosamide antibiotic lincomycin - share a common building unit, 
      4-alkyl-L-proline derivative (APD). APDs arise from L-tyrosine through a special 
      biosynthetic pathway. Its generally accepted scheme, however, did not comply with 
      current state of knowledge. Based on gene inactivation experiments and in vitro 
      functional tests with recombinant enzymes, we designed a new APD biosynthetic 
      scheme for the model of lincomycin biosynthesis. In the new scheme at least one 
      characteristic in each of five final biosynthetic steps has been changed: the 
      order of reactions, assignment of enzymes and/or reaction mechanisms. First, we 
      demonstrate that LmbW methylates a different substrate than previously assumed. 
      Second, we propose a unique reaction mechanism for the next step, in which a 
      putative gamma-glutamyltransferase LmbA indirectly cleaves off the oxalyl residue by 
      transient attachment of glutamate to LmbW product. This unprecedented mechanism 
      would represent the first example of the C-C bond cleavage catalyzed by a 
      gamma-glutamyltransferase, i.e., an enzyme that appears unsuitable for such activity. 
      Finally, the inactivation experiments show that LmbX is an isomerase indicating 
      that it transforms its substrate into a compound suitable for reduction by LmbY, 
      thereby facilitating its subsequent complete conversion to APD 
      4-propyl-L-proline. Elucidation of the APD biosynthesis has long time resisted 
      mainly due to the apparent absence of relevant C-C bond cleaving enzymatic 
      activity. Our proposal aims to unblock this situation not only for lincomycin 
      biosynthesis, but generally for all above mentioned groups of bioactive natural 
      products with biotechnological potential.
FAU - Jiraskova, Petra
AU  - Jiraskova P
AD  - Institute of Microbiology - Academy of Sciences of the Czech Republic Prague, 
      Czech Republic.
FAU - Gazak, Radek
AU  - Gazak R
AD  - Institute of Microbiology - Academy of Sciences of the Czech Republic Prague, 
      Czech Republic.
FAU - Kamenik, Zdenek
AU  - Kamenik Z
AD  - Institute of Microbiology - Academy of Sciences of the Czech Republic Prague, 
      Czech Republic.
FAU - Steiningerova, Lucie
AU  - Steiningerova L
AD  - Institute of Microbiology - Academy of Sciences of the Czech Republic Prague, 
      Czech Republic.
FAU - Najmanova, Lucie
AU  - Najmanova L
AD  - Institute of Microbiology - Academy of Sciences of the Czech Republic Prague, 
      Czech Republic.
FAU - Kadlcik, Stanislav
AU  - Kadlcik S
AD  - Institute of Microbiology - Academy of Sciences of the Czech Republic Prague, 
      Czech Republic.
FAU - Novotna, Jitka
AU  - Novotna J
AD  - Institute of Microbiology - Academy of Sciences of the Czech Republic Prague, 
      Czech Republic.
FAU - Kuzma, Marek
AU  - Kuzma M
AD  - Institute of Microbiology - Academy of Sciences of the Czech Republic Prague, 
      Czech Republic.
FAU - Janata, Jiri
AU  - Janata J
AD  - Institute of Microbiology - Academy of Sciences of the Czech Republic Prague, 
      Czech Republic.
LA  - eng
PT  - Journal Article
DEP - 20160307
PL  - Switzerland
TA  - Front Microbiol
JT  - Frontiers in microbiology
JID - 101548977
PMC - PMC4780272
OTO - NOTNLM
OT  - 4-propyl-L-proline
OT  - antibiotics
OT  - anticancer drug
OT  - hormaomycin
OT  - lincomycin
OT  - natural product biosynthesis
OT  - pyrrolobenzodiazepine
OT  - secondary metabolism
EDAT- 2016/03/26 06:00
MHDA- 2016/03/26 06:01
PMCR- 2016/03/07
CRDT- 2016/03/26 06:00
PHST- 2015/11/13 00:00 [received]
PHST- 2016/02/19 00:00 [accepted]
PHST- 2016/03/26 06:00 [entrez]
PHST- 2016/03/26 06:00 [pubmed]
PHST- 2016/03/26 06:01 [medline]
PHST- 2016/03/07 00:00 [pmc-release]
AID - 10.3389/fmicb.2016.00276 [doi]
PST - epublish
SO  - Front Microbiol. 2016 Mar 7;7:276. doi: 10.3389/fmicb.2016.00276. eCollection 
      2016.