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  • C12Y103/01053—(3S,4R)-3,4-dihydroxycyclohexa-1,5-diene-1,4-dicarboxylate dehydrogenase (1.3.1.53)
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  • C12Y114/1201—Benzoate 1,2-dioxygenase (1.14.12.10)
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  • C12Y114/13007—Phenol 2-monooxygenase (1.14.13.7)
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  • C12Y114/13—Oxidoreductases acting on paired donors, with incorporation or reduction of molecular oxygen (1.14) with NADH or NADPH as one donor, and incorporation of one atom of oxygen (1.14.13)
  • C12Y114/1302—2,4-Dichlorophenol 6-monooxygenase (1.14.13.20)
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  • C12Y114/13119—5-Epiaristolochene 1,3-dihydroxylase (1.14.13.119)

Definitions

• a microbial organism for producing terephthalate from biomass BACKGROUND Terephthalate also known as terephthalic acid or TPA
• terephthalic acid is a monomer which can be converted to polyethylene terephthalate and its copolyesters, also known as PET.
• PET is a raw material widely used in the packaging industry, for instance for making containers and bottles for food and beverages, and in the textile industry.
• TPA is obtained mainly from petrochemical sources, making its cost dependent on the price of oil.
• Different chemical processes have been proposed for converting carbon sources derived from biomass to terephthalate. Some processes involve only biological conversion steps, which are promoted by an enzymatic catalyst produced by microorganisms.
• Biomass treated to provide a fermentation feedstock is fermented with a microorganism to isobutanol, which is further catalytically converted to renewable p-xylene in three conversion steps.
• the p-xylene can then be oxidized to form terephthalic acid or terephthalate esters.
• WO2010148049 describes a method for converting cis, cis-muconic acid to terephtalate and its derivatives by means of a multi-step catalytic reaction.
• Muconic acid can be prepared from biomass, also by means of biological conversion.
• WO2011094131 describes a non-naturally occurring microorganism comprising pathways necessary for the production of (2 -hydroxy- 3-methyl-4-oxobutoxy)phosphonate, which can subsequently be converted to p-toluate, and which can then be converted to terephthalate pathway.
• the non-naturally occurring microbial organism comprises at least one of a first pathway comprising converting the carbon source to D-erythrose 4-phosphate (E4P) and phosphoenolpyruvate (PEP), converting E4P and PEP to 3-dehydroshikimate (DHS), and the at least a third enzyme expressed in a sufficient amount to produce a dihydroxybenzoate from DHS; a second pathway comprising the at least a first exogenous nucleic acid encoding the at least a first enzyme expressed in a sufficient amount to produce l,2-dihydroxy-3,5-cyclohexadiene-l,4-dicarboxylate (DCD) from the dihydroxybenzoate; and a third pathway comprising the at least a second exogenous nucleic acid encoding the at least a second enzyme expressed in a sufficient amount to produce terephthalate from l,2-dihydroxy-3,5-cyclohexadiene-l,4-dicarboxylate
• non-naturally occurring microbial organism may be cultured in aerobic or anaerobic culture conditions.
• Figure 2 presents a pathway for the conversion of glucose to terephthalate, according to a preferred embodiment of the invention.
• Figure 3 shows a schematic of a degradation pathway of TPA to PCA.
• Figures 4A and 4B show similar reactions in the KEGG database to parent reaction compared to its reversed reaction A) PCA->DCD, B) DCD->TPA.
• Figure 9 shows a schematic of a reaction catalyzed by benzoate 4-monooxygenase EC 1.14.13.12.
• Figure 10 shows a schematic of a reaction catalyzed by benzoate 1,2-dioxygenase EC 1.14.12.10.
• Figure 11 shows a target reaction that transforms DCD into TPA by reverse TPA 1,2- dioxygenase, according to one embodiment.
• Figure 12 shows a schematic of a reaction catalyzed by 3-dehydroquinate dehydratase (DHQD) EC 4.2.1.10.
• DHQD 3-dehydroquinate dehydratase
• Figure 13 shows a schematic of a reaction catalyzed by salicylaldehyde dehydrogenase EC 1.2.1.65.
• Figure 16 shows homology modeling for DCD dehydrogenase (yellow) from template 2hilA(green).
• Figures 20A, B show predicted mutations M240G for reversing DCD dehydrogenase, according to one embodiment.
• Figure 21 shows candidate mutations for benB-PCA interaction in order to show reverse DCD dehydrogenase activity, according to one embodiment.
• Figure 26 shows docking of DCD to enzyme structural model for benD, according to one embodiment.
• Figure 27 shows hot spots from the mutagenesis for benD-DCD interaction, according to one embodiment.
• Figure 28 shows a schematic of candidate predictions obtained through the tensor product methodfor the reverse reactions of enzymes EC 1.3.1.53 and EC 1.14.12.15.
• Figures 29a and 29b present a common pathway of aromatic compounds biosynthesis
• Figures 30a and 30b represents a pathway for the conversion of glucose to protocatechuate according to a preferred embodiment of the invention.
• Figure 31 represents a pathway for the conversion of glucose to protocatechuate according to another preferred embodiment of the invention.
• the non-naturally occurring microbial organism comprises at least one of the following metabolic pathways: a first pathway which converts a carbon source to at least a dihydroxybenzoate; a second pathway which converts at least a fraction of the dihydroxybenzoate to l,2-dihydroxy-3,5- cyclohexadiene-l,4-dicarboxylate; and a third pathway which converts at least a fraction of the l,2-dihydroxy-3,5-cyclohexadiene-l,4-dicarboxylate to terephthalate.
• the dihydroxybenzoate is protocatechuate.
• l,2-dihydroxy-3,5-cyclohexadiene-l,4-dicarboxylate will also be indicated by DCD
• protocatechuate will also be indicated by PC A
• terephthalate will also be indicated by TP A.
• Terephthalate is a chemical compound having the molecular formula CgH 4 0 4 " (IUPAC name terephthalate), which is the ionized form of terephthalic acid, also referred to as p- phthalic acid or TPA, and it is understood that terephthalate and terephthalic acid can be used interchangeably throughout to refer to the compound in any of its neutral or ionized forms, including any salt forms thereof. It is understood by those skilled in the art that the specific form will depend on the pH.
• the chemical structure of terephthalate in acidic form is represented in Figure 1(a).
• Dihydroxybenzoate is a class of aromatic chemical compounds having the molecular formula C 7 H 6 0 4 and the general chemical structure represented in Figure 1(b).
• dihydroxybenzoate is protocatechuate and is represented as 3,4- dihydroxybenzoic acid.
• the chemical structure of protocatechuate is reported in Figure 1(c).
• DCD is a chemical compound having the molecular formula C ⁇ H Oe and the chemical structure is represented in Figure 1(d). DCD is not an aromatic compound.
• a production of terephthalate is represented by the pathway shown in Figure 2.
• the carbon source is represented by glucose.
• dihydroxybenzoate and PCA may be accumulated in the non- naturally occurring microbial organism.
• a product is accumulated in the non-naturally occurring microbial organism, it is meant that the product is made available inside the cell of the microbial organism.
• the product is accumulated in the non-naturally occurring microbial organism, and is not further subjected to biochemical conversion, it may be present in the microbial organism and it can be detected and harvested.
• At least a fraction of the product accumulated in the non-naturally occurring microbial organism is further subjected to biochemical conversion reactions, it may or may not be present and detectable, depending on the intracellular condition, the reaction kinetics, and the fraction of the product involved in the subsequent conversion.
• the described product(s) may be secreted from the non-naturally occurring microbial organism, or a combination of accumulation and secretion of the described products may occur.
• a product(s) when secreted, it can be harvested from a medium external to the non-naturally occurring microbial organism, such as the culture medium.
• the non-naturally occurring microbial organism may be fed with the carbon source with subsequent conversion to DCD through the formation of intermediate compounds, comprising at least a dihydroxybenzoate.
• the carbon source may be obtained from a biomass, for example, from a ligno-cellulosic feedstock, which may be further subjected to a pretreatment and to an enzymatic hydrolysis process.
• non-naturally occurring microbial organism or microorganism of the invention means that the microbial organism has at least one genetic alteration not normally found in a naturally occurring strain of the referenced species, including naturally-occurring strains of the referenced species.
• Genetic alterations include, for example, modifications introducing expressible nucleic acids encoding metabolic polypeptides, other nucleic acid addi- tions, nucleic acid deletions and/or other functional disruption of the microbial organism's genetic material. Such modifications include, for example, coding regions and functional fragments thereof, for heterologous, homologous or both heterologous and homologous polypeptides for the referenced species.
• Additional modifications include, for example, non-coding regulatory regions in which the modifications alter expression of a gene or op- eron.
• Exemplary metabolic polypeptides include enzymes within a dihydroxybenzoate, PCA and TPA biosynthetic pathway.
• a metabolic modification refers to a biochemical reaction that is altered from its naturally occurring state. Therefore, non-naturally occurring microorganisms can have genetic modifications to nucleic acids encoding metabolic polypeptides, or functional fragments thereof.
• the present invention discloses metabolic pathways that can be designed and inserted in a micro-organism to achieve biosynthesis of terephthalate and/or DCD in cells or organisms. For example, biosynthetic production of terephthalate can be confirmed by construction of strains having the designed metabolic genotype.
• These metabolically engineered cells or organisms also can be subjected to adaptive evolution to further augment terephthalate bio- synthesis, including under conditions approaching theoretical maximum growth.
• Exogenous as used herein is intended to mean that the referenced molecule or the referenced activity is introduced into the host microbial organism.
• the molecule can be introduced, for example, by introduction of an encoding nucleic acid into the host genetic mate- rial such as by integration into a host chromosome or as non-chromosomal genetic material such as a plasmid. Therefore, the term as it is used in reference to expression of an encoding nucleic acid refers to introduction of the encoding nucleic acid in an expressible form into the microbial organism. When used in reference to a biosynthetic activity, the term refers to an activity that is introduced into the host reference organism.
• the source can be, for example, a homologous or heterologous encoding nucleic acid that expresses the referenced activity following introduction into the host microbial organism. Therefore, the term “endogenous” refers to a referenced molecule or activity that is present in the host. Similarly, the term when used in reference to expression of an encoding nucleic acid refers to expression of an encoding nucleic acid contained within the microbial organism.
• heterologous refers to a molecule or activity derived from a source other than the referenced species whereas “homologous” refers to a molecule or activity derived from the host microbial organism.
• exogenous expression of an encoding nucleic acid of the invention can utilize either or both a heterologous or homologous encoding nucleic acid. It is understood that when more than one exogenous nucleic acid is included in a microbial organism, that the more than one exogenous nucleic acids refers to the referenced encoding nucleic acid or biosynthetic activity, as discussed above. It is further understood, as dis- closed herein, that such more than one exogenous nucleic acids can be introduced into the host microbial organism on separate nucleic acid molecules, on polycistronic nucleic acid molecules, or a combination thereof, and still be considered as more than one exogenous nucleic acid.
• a microbial organism can be engineered to express two or more exogenous nucleic acids encoding a desired pathway enzyme or protein.
• two exogenous nucleic acids encoding a desired activity are introduced into a host microbial organism, it is understood that the two exogenous nucleic acids can be introduced as a single nucleic acid, for example, on a single plasmid, on separate plasmids, can be integrated into the host chromosome at a single site or multiple sites, and still be considered as two exogenous nucleic acids.
• coli is a particularly useful host organisms since it is a well characterized microbial organism suitable for genetic engineering.
• Other particularly useful host organisms include yeast such as Saccharomyces cerevisiae. It is understood that any suitable microbial host organism can be used to introduce metabolic and/or genetic modifications to produce a desired product.
• a coding region is isolated by first preparing a genomic DNA library or a cDNA library, and second, identifying the coding region in the genomic DNA library or cDNA library, such as by probing the library with a labeled nucleotide probe that is at least partially homologous with the coding region, determining whether expression of the coding region imparts a detectable phenotype to a library microorganism comprising the coding region, or amplifying the desired sequence by PCR.
• Other techniques for isolating the coding region may also be used.
• the desired coding region is incorporated into the recipient organism in such a manner that the encoded enzyme is produced by the organism in functional form. That is, the coding region is inserted into an appropriate vector and operably linked to an appropriate promoter on the vector.
• An enzyme which catalyzes a reaction for converting a first compound to a second compound may be tuned to catalyze a reverse reaction to convert the second compound to the first compound. That is, the compound which is the reagent in a direct reaction, may be- come the product in the reverse reaction.
• the enzyme may, under certain conditions, catalyze the reverse reaction of a reaction catalyzed by the same enzyme. For instance, this may be done by genetically modification of a micro-organism or modification of the culture medium in such a way that the reverse reaction is promoted. In a similar way, a pathway comprising many reactions may be reverted by reverting each single reaction which forms the pathway.
• new biosynthetic pathways for producing TPA and/or DCD were identified.
• molecular graph-based methods for the modeling of enzymatic activity and specificity and for building predictors were used.
• the predictors are based on statistical inference and machine learning methods.
• the results are presented in two broad categories - identification of enzymes which are suitable for the desired reactions, and identification of mutations within the enzyme which increases the suitability of the enzyme to perform the desired reaction.
• the starting point for the new biosynthetic pathways is the degradation pathway from TPA to PCA, taking as reference its characterization and gene cluster identification for Comamonas sp.
• candidate enzymes for the target reactions were determined using an annotation tool for reactions in the RetroPathtool (Carbonell et al, 2011).
• the method is based on a kernel-based predictor from the tensor product of the reactions molecular signatures and the string kernel of enzyme sequences (Faulon et al, 2008), and employed a computing cluster of 8 nodes x 12 cores (76 CPUs) and two metabolic databases KEGG (release 50) and Metacyc (release 16.0).
• This analysis screened 566117 enzyme sequences in KEGG and 5418 enzyme sequences in MetaCyc, as well as 6746 reactions in KEGG and 4392 re- actions in MetaCyc.
• Tensor product this score is the output from our molecular signature -based predictor (Faulon et al, 2008), (Carbonell and Faulon, 2010). A higher value of this score can be interpreted as a higher feasibility for the enzyme to be able to catalyze efficiently the target reaction; and 2) Closeness of se- quence to positive set: this score provides the maximum similarity between the predicted sequence and the sequences in the positive set. It is used in order to control the maximum allowed departure from the positive set that is screened in the sequence space.
• This en- zyme is highly promiscuous: it transforms phenol to catechol ( Figure 8), as well as toluene to o-cresol, 3-cresol to 2,3-dihyroxytoluene, 4-cresol to 4-methylcatechol, o-cresol to 2,3- dihydroytoluene,resorcinol to benzene- 1,2,4-triol.
• the top ranked gene is the one from Arthrobacteraurescens; it codes a 644 amino acids protein (Mongodin et al, 2006).
• gill 11024961 4-hydroxythreonine-4-phosphate dehydrogenase [Rhodococcusjostii RHA1] gil377811638 unnamed protein product [Burkholderia sp. YI23]
• the disclosed terephthalate pathway comprises a first pathway for converting the carbon source to dihydroxybenzoate; a second pathway for converting at least a fraction of the dihydroxybenzoate to at least DCD; and a third pathway for converting at least a fraction of DCD to at least TPA.
• the disclosed terephthalate pathway comprises reactions for accumulating in the non-naturally occurring microbial organism at least the two intermediate products, dihydroxybenzoate and DCD. Other intermediate products may be formed in the pathway.
• the exogenous nucleic acid is aroZ from Klebsiella pneumonia.
• the first pathway further comprises an enzyme encoded by an exogenous nucleic acid that blocks the conversion of DHS to chorismate.
• Such mutants are unable to catalyze the conversion of 3- dehydro shikimate (DHS) to chorismate due to a mutation in one or more of the genes encoding shikimate dehydrogenase, shikimate kinase, EPSP synthase and chorismate syn- thase, and will thus accumulate elevated intracellular levels of DHS.
• DHS 3- dehydro shikimate
• coli AB2834 is unable to catalyze the conversion of 3-dehydroshikimate (DHS) to shikimic acid due to a mutation in the aroE locus which encodes shikimate dehydrogenase. Similar- ly E. coli AB2829 and E. coli AB2849 also result in increased intracellular levels of DHS.
• DHS 3-dehydroshikimate
• Pre-treatment techniques are well known in the art and include physical, chemical, and bio- logical pre-treatment, or any combination thereof.
• pretreatment of ligno-cellulosic material is carried out as a batch or continuous process.
• starch hydrolysis is primarily glucose, maltose, maltotriose, [alpha] -dextrin and varying amounts of oligosaccharides.
• proteolytic enzymes may prevent flocculation of the microorganism and may generate amino acids available to the microorganism.

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