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Zhao, Huimin Johannes, Tyler William 2015-09-25T20:43:37Z 2015-09-25T20:43:37Z 10000-01-01 2008 2008 Another area in which biocatalysts are increasingly being used is in the production of small secondary metabolites, particularly antibiotics. Phosphonates are a small but growing class of compounds with many useful therapeutic properties. In particular, the phosphonates fosmidomycin and FR-900098 represent a new class of antimalarial compounds that can be used to inhibit the nonmevalonate pathway for isoprenoid biosynthesis in the malaria-causing parasite Plasmodium falciparum. Although no biosynthetic pathway for fosmidomycin has been elucidated as of yet, the biosynthetic pathway for FR-900098 has been cloned from Streptomyces rubellomurinus and heterologously expressed in Streptomyces lividans. In this work, we have created an E. coli strain capable of producing FR-900098 and have worked to decipher the late steps of FR-900098 biosynthesis. These studies revealed that the late steps of FR-900098 biosynthesis involve a unique bifunctional nucleotide transferase-decarboxylase (FrbH), an N-acetyltransferase (FrbF), a novel amide hydroxylase (FrbG), and a promiscuous nucleotide hydrolase (FrbI). The presence of cytidine 5'-monophosphate (CMP) conjugated phosphonate intermediates in the pathway also gives fascinating new insights into how phosphonate antibiotic pathways evolve to protect the host organism from the effects of toxic intermediates and promiscuous enzymes. Made available in DSpace on 2015-09-25T20:43:37Z (GMT). No. of bitstreams: 2 license.txt: 4848 bytes, checksum: 96035ab3f5e1c23cc7138a224ce498bd (MD5) 3314808.pdf: 2241315 bytes, checksum: eb5bbc746a0dbd546fc4767b0f991135 (MD5) Previous issue date: 2008 Embargo set by: Seth Robbins for item 83689 Lift date: Forever Reason: Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs U of I Only 150 p. Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2008. http://hdl.handle.net/2142/82408 (MiAaPQ)AAI3314808 eng Engineering, Chemical Directed Evolution of Phosphite Dehydrogenase and Engineered Biosynthesis of Fr-900098 text Chemical Engineering Chemical Engineering University of Illinois at Urbana-Champaign Dissertation Ph.D.