PMID- 30320257
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200930
IS  - 2470-1343 (Print)
IS  - 2470-1343 (Electronic)
IS  - 2470-1343 (Linking)
VI  - 3
IP  - 9
DP  - 2018 Sep 30
TI  - Synthetic Enzymology and the Fountain of Youth: Repurposing Biology for 
      Longevity.
PG  - 11050-11061
LID - 10.1021/acsomega.8b01620 [doi]
AB  - Caloric restriction (CR) is an intervention that can increase maximal lifespan in 
      organisms, but its application to humans remains challenging. A more feasible 
      approach to achieve lifespan extension is to develop CR mimetics that target 
      biochemical pathways affected by CR. Recent studies in the engineering and 
      structural characterization of polyketide synthases (PKSs) have facilitated their 
      use as biocatalysts to produce novel polyketides. Here, we show that by 
      establishing a combinatorial biosynthetic route in Escherichia coli and exploring 
      the substrate promiscuity of a mutant PKS from alfalfa, 413 potential anti-ageing 
      polyketides were biosynthesized. In this approach, novel acyl-coenzyme A (CoA) 
      precursors generated by promiscuous acid-CoA ligases were utilized by PKS to 
      generate polyketides which were then fed to Caenorhabditis elegans to study their 
      potential efficacy in lifespan extension. It was found that CR mimetics like 
      resveratrol can counter the age-associated decline in mitochondrial function and 
      increase the lifespan of C. elegans. Using the mitochondrial respiration profile 
      of C. elegans supplemented for 8 days with 50 muM resveratrol as a blueprint, we 
      can screen our novel polyketides for potential CR mimetics with improved potency. 
      This study highlights the utility of synthetic enzymology in the development of 
      novel anti-ageing therapeutics.
FAU - Lim, Yan Ping
AU  - Lim YP
AD  - Department of Biochemistry, Yong Loo Lin School of Medicine, National University 
      of Singapore, 8 Medical Drive, 117597, Singapore.
AD  - NUS Synthetic Biology for Clinical and Technological Innovation, Centre for Life 
      Sciences, and Singapore Lipidomics Incubator, Life Sciences Institute, National 
      University of Singapore, 28 Medical Drive, 117456, Singapore.
FAU - Go, Maybelle K
AU  - Go MK
AD  - Department of Biochemistry, Yong Loo Lin School of Medicine, National University 
      of Singapore, 8 Medical Drive, 117597, Singapore.
AD  - NUS Synthetic Biology for Clinical and Technological Innovation, Centre for Life 
      Sciences, and Singapore Lipidomics Incubator, Life Sciences Institute, National 
      University of Singapore, 28 Medical Drive, 117456, Singapore.
FAU - Raida, Manfred
AU  - Raida M
AD  - Department of Biochemistry, Yong Loo Lin School of Medicine, National University 
      of Singapore, 8 Medical Drive, 117597, Singapore.
AD  - NUS Synthetic Biology for Clinical and Technological Innovation, Centre for Life 
      Sciences, and Singapore Lipidomics Incubator, Life Sciences Institute, National 
      University of Singapore, 28 Medical Drive, 117456, Singapore.
FAU - Inoue, Takao
AU  - Inoue T
AD  - Department of Biochemistry, Yong Loo Lin School of Medicine, National University 
      of Singapore, 8 Medical Drive, 117597, Singapore.
FAU - Wenk, Markus R
AU  - Wenk MR
AD  - Department of Biochemistry, Yong Loo Lin School of Medicine, National University 
      of Singapore, 8 Medical Drive, 117597, Singapore.
AD  - NUS Synthetic Biology for Clinical and Technological Innovation, Centre for Life 
      Sciences, and Singapore Lipidomics Incubator, Life Sciences Institute, National 
      University of Singapore, 28 Medical Drive, 117456, Singapore.
FAU - Keasling, Jay D
AU  - Keasling JD
AD  - Department of Chemical & Biomolecular Engineering, University of California at 
      Berkeley, 5885 Hollis Street, Emeryville, California 94608, United States.
FAU - Chang, Matthew W
AU  - Chang MW
AD  - Department of Biochemistry, Yong Loo Lin School of Medicine, National University 
      of Singapore, 8 Medical Drive, 117597, Singapore.
AD  - NUS Synthetic Biology for Clinical and Technological Innovation, Centre for Life 
      Sciences, and Singapore Lipidomics Incubator, Life Sciences Institute, National 
      University of Singapore, 28 Medical Drive, 117456, Singapore.
FAU - Yew, Wen Shan
AU  - Yew WS
AD  - Department of Biochemistry, Yong Loo Lin School of Medicine, National University 
      of Singapore, 8 Medical Drive, 117597, Singapore.
AD  - NUS Synthetic Biology for Clinical and Technological Innovation, Centre for Life 
      Sciences, and Singapore Lipidomics Incubator, Life Sciences Institute, National 
      University of Singapore, 28 Medical Drive, 117456, Singapore.
LA  - eng
PT  - Journal Article
DEP - 20180912
PL  - United States
TA  - ACS Omega
JT  - ACS omega
JID - 101691658
PMC - PMC6173508
COIS- The authors declare no competing financial interest.
EDAT- 2018/10/16 06:00
MHDA- 2018/10/16 06:01
PMCR- 2018/09/12
CRDT- 2018/10/16 06:00
PHST- 2018/07/11 00:00 [received]
PHST- 2018/08/30 00:00 [accepted]
PHST- 2018/10/16 06:00 [entrez]
PHST- 2018/10/16 06:00 [pubmed]
PHST- 2018/10/16 06:01 [medline]
PHST- 2018/09/12 00:00 [pmc-release]
AID - 10.1021/acsomega.8b01620 [doi]
PST - ppublish
SO  - ACS Omega. 2018 Sep 30;3(9):11050-11061. doi: 10.1021/acsomega.8b01620. Epub 2018 
      Sep 12.