The RAVEN Toolbox and Its Use for Generating a Genome-scale Metabolic Model for Penicillium chrysogenum
Figure 7
Integrative analysis of a high and a low producing strain.
Depicts synthesis pathways of penicillin and important precursors. Green boxes correspond to reactions identified as being transcriptionally controlled and up-regulated by the algorithm (see text). Metabolites around which significant transcriptional changes occur compared to a low producing strain are colored red. SC: side chain (e. g. the precursor molecule phenylacetic acid). The biosynthesis of penicillin starts with the condensation of the three amino acids α-aminoadipate (an intermediate in the L-lysine biosynthesis pathway), L-cystein, and L-valine to form the tripeptide ACV. ACV is further converted to isopenicillin N. For the industrially relevant types of penicillin a side-chain is supplied to the media. This side-chain is activated by ligation to coenzyme A. In the last step of penicillin biosynthesis an acyl transferase exchanges the α-aminoadipate moiety of isopenicillin N with the side-chain, thereby generating penicillin and regenerating α-aminoadipate. Since L-cystein is a sulfur-containing amino acid penicillin production is also tightly associated with sulfur metabolism. The corresponding model IDs for the enzymes are indicated within parentheses. [1] homocitrate synthase (r0683); [2] homocitrate dehydrase (r0684); [3] homoaconitate hydrase (r0685); [4] homoisocitrate dehydrogenase (r0688); [5] α-aminoadipate aminotransferase (r0689); [6] homoserine transacetylase (r0600); [7] O-acetylhomoserine sulfhydrylase (r0601); [8] cystathione-β-synthase (r0632); [9] cystathione-γ-lyase (r0606); [10] acetate CoA ligase (r0025); [11] acetolactate synthase (r0465); [12] ketol-acid reductoisomerase (r0653); [13] dihydroxy acid dehydrase (r0656); [14] branched chain amino acid transferase (r0648); [15] ACV synthase (r0814); [16] isopenicillin N synthase (r0812); [17] acyl CoA ligase (side chain dependent, reaction is for phenylacetate CoA ligase) (r0747); [18] isopenicillin N N-acyltransferase (r0813); [19] sulfate permease (r1408); [20] sulfate adenyl transferase (r1151); [21] adenyl sulfate kinase (r1147); [22] phosphoadenyl sulfate reductase (r1148); [23] sulfite reductase (r1149); [24] thioredoxin reductase (r0419); [25] 3′(2′),5′-bisphosphate nucleotidase (r1150).