Pathways

Tetracyclines are aromatic polyketide antibiotics produced via type II polyketide synthases and possess several antibiotic drug properties that work against the activity of Gram-positive and negative bacterial pathogens and are also used to treat several types of bacterial infections in the body. They are natural polyketides produced by actinomycete bacteria like Kitasatospora aureofaciens and are unique by their tetracyclic ring structure and a richly substituted A ring. This pathway shows biosynthesis of naturally occurring tetracyclines (oxytetracycline, tetracycline and chlortetracycline) via the common intermediate anhydrotetracycline. Four genes: oxyE, oxyL, oxyQ, oxyT encode the enzymes that are involved in the modifications that generate anhydrotetracycline. The final two enzymes in the pathway are monooxygenases that are encoded by the gene oxyS and an F420-dependent dehydrogenase encoded by oxyR. OxyS catalyzes two successive monooxygenation reactions where one variation leads to the formation of tetracycline and the other leads to the formation of oxytetracycline. Tetracycline also leads to the formation of chlortetracycline via the enzyme flavin reductase (NADH).

Metabolites of Tetracycline are predicted with biotransformer.

Metabolites of Tetradecyl hydrogen sulfate (ester) are predicted with biotransformer.

The biosynthesis of tetrahydrofolate begins with guanosine triphosphate interacting with water through GTP-cyclohydrlase resulting in the release of a formic acid, a hydrogen ion and a dihydroneopterin triphosphate. The latter compound then reacts with water in a spontaneous reaction resulting in the release of pyrophosphate, hydrogen ion and dihydroneopterinphosphate. Dihydroneopterin phosphate then reacts spontaneously with water resulting in the release of phosphate and 7,8-dihydroneopterin. This compound reacts wuth a folic acid synthesis enzyme resulting in the release of glycoaldehyde and 6-hydroxymethyl-7,8-dihydropterin. The latter compound is then diphosphorylated through an ATP driven folic acid synthesis resulting in the release of AMP, a hydrogen ion and 6-hydroxymethyl-7,8-dihydropterin diphosphate. This compound reacts with p-Aminobenzoic acid that is release from chorismate, the reaction happens through a folic acid synthesis resulting in the pyrophosphate and 7,8-dihydropteric acid. The latter compound reacts with glutamic acid through an ATP driven folic acid synthesis 3 resulting in the release of hydrogen ion, a phosphate, ADP and a 7,8-dihydrofolate monoglutamate. The latter compound reacts with a hydrogen ion through a NADPH through a dihydrofolate reductase resulting in the release of NADP and tetrahydrofolate. This compound can also be a result of 5,10 methenyltetrahydrofolic acid reacting with water through a mitochondrials c1-tetrahydrofolate synthase which releases a 10-formyltetrahydrofolate. This compound in turn reacts with a 5-phosphoribosyl-N-formylglycinamide through a glycinamide ribotide transformylase resulting in the release of a tetrahydrofolate and a 5'phosphoribosyl-N-fromylglycinamide.

This pathway demonstrates the biosynthesis of tetrahydromonapterin in E.coli. However, it is still unclear about biological role of tetrahydromonapterin. GTP cyclohydrolase 1 generates formic acid and 7,8-dihydroneopterin 3'-triphosphate with cofactor GTP and water. 7,8-dihydroneopterin 3'-triphosphate is converted to dihydromonapterin-triphosphate by d-erythro-7,8-dihydroneopterin triphosphate epimerase (folX). Later, dihydromonapterin-triphosphate is hydroxylated to dihydromethysticin, and eventually form tetrahydromonapterin via dihydromonapterin reductase (folM) with cofactor NADPH.