2.02012-10-10 12:21:46 -06002015-06-03 17:26:08 -0600ECMDB23199M2MDB003589UDP-4-Deoxy-4-formamido-beta-L-arabinoseUDP-4-Deoxy-4-formamido-beta-L-arabinose is an intermediate in the polymixin resistance pathway. It is a substrate for the enzyme Bifunctional polymyxin resistance protein ArnA that catalyzes the oxidative decarboxylation of UDP-glucuronic acid (UDP-GlcUA) to UDP-4-keto-arabinose (UDP-Ara4O) and the addition of a formyl group to UDP-4-amino-4-deoxy-L-arabinose (UDP-L-Ara4N) to form UDP-L-4-formamido-arabinose (UDP-L-Ara4FN). The modified arabinose is attached to lipid A and is required for resistance to polymyxin and cationic antimicrobial peptides. Some Gram-negative bacteria, specifically Salmonella typhimurium and Escherichia coli, can become resistant to polymyxin by the modification of their lipid A structure via the attachment of 4-amino-4-deoxy-L-arabinopyranose (L-Ara4N) groups to one or more phosphate groups. This addition causes an absolute increase in lipid A charge, thus lowering the affinity of positively charged polymyxins.(2R,3S,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-3,4-dihydroxytetrahydro-2-furanylmethyl (2R,3R,4S,5S)-5-formamido-3,4-dihydroxytetrahydro-2H-pyran-2-yl dihydrogen diphosphate (non-preferre
d name)(2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydro-1(2H)-Pyrimidinyl)-3,4-dihydroxytetrahydro-2-furanylmethyl (2R,3R,4S,5S)-5-formamido-3,4-dihydroxytetrahydro-2H-pyran-2-yl dihydrogen diphosphoric acid (non-preferre
D name)(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-ylmethoxy-hydroxyphosphoryl (2R,3R,4S,5S)-5-formamido-3,4-dihydroxyoxan-2-yl hydrogen phosphate(2R,3S,4R,5R)-5-(2,4-Dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-ylmethoxy-hydroxyphosphoryl (2R,3R,4S,5S)-5-formamido-3,4-dihydroxyoxan-2-yl hydrogen phosphoric acidUDP-4-Deoxy-4-formamido-b-L-arabinoseUDP-4-Deoxy-4-formamido-β-L-arabinoseUDP-b-L-Ara4fnUDP-beta-L-Ara4FNUDP-L-Ara4FNUDP-β-L-Ara4fnUridine 5'-diphospho-b-(4-deoxy-4-formamido-L-arabinose)Uridine 5'-diphospho-beta-(4-deoxy-4-formamido-L-arabinose)Uridine 5'-diphospho-β-(4-deoxy-4-formamido-L-arabinose)C15H23N3O16P2563.3011563.055354727N-[(3S,4S,5R,6R)-6-({[({[(2R,3S,4R,5R)-3,4-dihydroxy-5-(4-hydroxy-2-oxo-1,2-dihydropyrimidin-1-yl)oxolan-2-yl]methoxy}(hydroxy)phosphoryl)oxy](hydroxy)phosphoryl}oxy)-4,5-dihydroxyoxan-3-yl]carboximidic acidudp-L-ara4FN[H][C@]1(COP(O)(=O)OP(O)(=O)O[C@@]2([H])OC[C@]([H])(N=CO)[C@]([H])(O)[C@@]2([H])O)O[C@@]([H])(N2C=CC(O)=NC2=O)[C@]([H])(O)[C@]1([H])OInChI=1S/C15H23N3O16P2/c19-5-16-6-3-30-14(12(24)9(6)21)33-36(28,29)34-35(26,27)31-4-7-10(22)11(23)13(32-7)18-2-1-8(20)17-15(18)25/h1-2,5-7,9-14,21-24H,3-4H2,(H,16,19)(H,26,27)(H,28,29)(H,17,20,25)/t6-,7+,9-,10+,11+,12+,13+,14+/m0/s1QGYFHZBDXXNYAX-RTXATJJPSA-Nlogp-1.49logs-1.73solubility1.04e+01 g/llogp-4.6pka_strongest_acidic1.61pka_strongest_basic2.53iupacN-[(3S,4S,5R,6R)-6-({[({[(2R,3S,4R,5R)-3,4-dihydroxy-5-(4-hydroxy-2-oxo-1,2-dihydropyrimidin-1-yl)oxolan-2-yl]methoxy}(hydroxy)phosphoryl)oxy](hydroxy)phosphoryl}oxy)-4,5-dihydroxyoxan-3-yl]carboximidic acidaverage_mass563.3011mono_mass563.055354727smiles[H][C@]1(COP(O)(=O)OP(O)(=O)O[C@@]2([H])OC[C@]([H])(N=CO)[C@]([H])(O)[C@@]2([H])O)O[C@@]([H])(N2C=CC(O)=NC2=O)[C@]([H])(O)[C@]1([H])OformulaC15H23N3O16P2inchiInChI=1S/C15H23N3O16P2/c19-5-16-6-3-30-14(12(24)9(6)21)33-36(28,29)34-35(26,27)31-4-7-10(22)11(23)13(32-7)18-2-1-8(20)17-15(18)25/h1-2,5-7,9-14,21-24H,3-4H2,(H,16,19)(H,26,27)(H,28,29)(H,17,20,25)/t6-,7+,9-,10+,11+,12+,13+,14+/m0/s1inchikeyQGYFHZBDXXNYAX-RTXATJJPSA-Npolar_surface_area287.16refractivity107.95polarizability46.42rotatable_bond_count9acceptor_count15donor_count8physiological_charge-1formal_charge0Amino sugar and nucleotide sugar metabolism IIIThe synthesis of amino sugars and nucleotide sugars starts with the phosphorylation of N-Acetylmuramic acid (MurNac) through its transport from the periplasmic space to the cytoplasm. Once in the cytoplasm, MurNac and water undergo a reversible reaction through a N-acetylmuramic acid 6-phosphate etherase, producing a D-lactic acid and N-Acetyl-D-Glucosamine 6-phosphate. This latter compound can also be introduced into the cytoplasm through a phosphorylating PTS permase in the inner membrane that allows for the transport of N-Acetyl-D-glucosamine from the periplasmic space. N-Acetyl-D-Glucosamine 6-phosphate can also be obtained from chitin dependent reactions. Chitin is hydrated through a bifunctional chitinase to produce chitobiose. This in turn gets hydrated by a beta-hexosaminidase to produce N-acetyl-D-glucosamine. The latter undergoes an atp dependent phosphorylation leading to the production of N-Acetyl-D-Glucosamine 6-phosphate.
N-Acetyl-D-Glucosamine 6-phosphate is then be deacetylated in order to produce Glucosamine 6-phosphate through a N-acetylglucosamine-6-phosphate deacetylase. This compound is then deaminased into Beta-D-fructofuranose 6-phosphate through a glucosamine-6-phosphate deaminase.
Beta-D-fructofuranose 6-phosphate is isomerized into a beta-D-glucose 6-phosphate through a glucose-6-phosphate isomerase. The compound is then isomerized by a putative beta-phosphoglucomutase to produce a beta-D-glucose 1-phosphate. This compound enters the nucleotide sugar metabolism through uridylation resulting in a UDP-glucose. UDP-glucose is then dehydrated through a UDP-glucose 6-dehydrogenase to produce a UDP-glucuronic acid. This compound undergoes a NAD dependent reaction through a bifunctional polymyxin resistance protein to produce UDP-Beta-L-threo-pentapyranos-4-ulose. This compound then reacts with L-glutamic acid through a UDP-4-amino-4-deoxy-L-arabinose--oxoglutarate aminotransferase to produce an oxoglutaric acid and UDP-4-amino-4-deoxy-beta-L-arabinopyranose
The latter compound interacts with a N10-formyl-tetrahydrofolate through a bifunctional polymyxin resistance protein ArnA, resulting in a tetrahydrofolate, a hydrogen ion and a UDP-4-deoxy-4-formamido-beta-L-arabinopyranose, which in turn reacts with a product of the methylerythritol phosphate and polysoprenoid biosynthesis pathway, di-trans,octa-cis-undecaprenyl phosphate to produce a 4-deoxy-4-formamido-alpha-L-arabinopyranosyl ditrans, octacis-undecaprenyl phosphate.
Alpha-D-glucose is introduced into the cytoplasm through a glucose PTS permease, which phosphorylates the compound in order to produce an alpha-D-glucose 6-phosphate. This compound is then modified through a phosphoglucomutase 1 to yield alpha-D-glucose 1-phosphate. This compound can either be adenylated to produce ADP-glucose or uridylylated to produce galactose 1-phosphate through glucose-1-phosphate adenyllyltransferase and galactose-1-phosphate uridylyltransferase respectively.PW000895MetabolicOne Carbon Pool by Folate IDihydrofolic acid, a product of the folate biosynthesis pathway, can be metabolized by multiple enzymes.
Dihydrofolic acid can be reduced by a NADP-driven dihydrofolate reductase resulting in a NADPH, hydrogen ion and folic acid.
Dihydrofolic acid can also be reduced by an NADPH-driven dihydrofolate reductase resulting in a NADP and a tetrahydrofolic acid. Folic acid can also produce a tetrahydrofolic acid through a NADPH-driven dihydrofolate reductase.
Dihydrofolic acid also interacts with 5-thymidylic acid through a thymidylate synthase resulting in the release of dUMP and 5,10-methylene-THF
Tetrahydrofolic acid can be converted into 5,10-methylene-THF through two different reversible reactions.
Tetrahydrofolic acid interacts with a S-Aminomethyldihydrolipoylprotein through a aminomethyltransferase resulting in the release of ammonia, a dihydrolipoylprotein and 5,10-Methylene-THF
Tetrahydrofolic acid interacts with L-serine through a glycine hydroxymethyltransferase resulting in a glycine, water and 5,10-Methylene-THF.
The compound 5,10-methylene-THF reacts with an NADPH dependent methylenetetrahydrofolate reductase [NAD(P)H] resulting in NADP and 5-Methyltetrahydrofolic acid. This compound interacts with homocysteine through a methionine synthase resulting in L-methionine and tetrahydrofolic acid.
Tetrahydrofolic acid can be metabolized into 10-formyltetrahydrofolate through 4 different enzymes:
1.- Tetrahydrofolic acid interacts with FAICAR through a phosphoribosylaminoimidazolecarboxamide formyltransferase resulting in a 1-(5'-Phosphoribosyl)-5-amino-4-imidazolecarboxamide and a 10-formyltetrahydrofolate
2.-Tetrahydrofolic acid interacts with 5'-Phosphoribosyl-N-formylglycinamide through a phosphoribosylglycinamide formyltransferase 2 resulting in a Glycineamideribotide and a 10-formyltetrahydrofolate
3.-Tetrahydrofolic acid interacts with Formic acid through a formyltetrahydrofolate hydrolase resulting in water and a 10-formyltetrahydrofolate
4.-Tetrahydrofolic acid interacts with N-formylmethionyl-tRNA(fMet) through a 10-formyltetrahydrofolate:L-methionyl-tRNA(fMet) N-formyltransferase resulting in a L-methionyl-tRNA(Met) and a 10-formyltetrahydrofolate
10-formyltetrahydrofolate can interact with a hydrogen ion through a bifunctional 5,10-methylene-tetrahydrofolate dehydrogenase resulting in water and
5,10-methenyltetrahydrofolic acid.
Tetrahydrofolic acid can be metabolized into 5,10-methenyltetrahydrofolic acid by reacting with a
5'-phosphoribosyl-a-N-formylglycineamidine through a phosphoribosylglycinamide formyltransferase 2 resulting in water, glycineamideribotide and 5,10-methenyltetrahydrofolic acid. The latter compound can either interact with water through an aminomethyltransferase resulting in a N5-Formyl-THF, or it can interact with a NADPH driven bifunctional 5,10-methylene-tetrahydrofolate dehydrogenase resulting in a NADP and 5,10-Methylene THF.
PW001735Metabolicpolymyxin resistanceUDP-glucuronic acid compound undergoes a NAD dependent reaction through a bifunctional polymyxin resistance protein to produce UDP-Beta-L-threo-pentapyranos-4-ulose. This compound then reacts with L-glutamic acid through a UDP-4-amino-4-deoxy-L-arabinose--oxoglutarate aminotransferase to produce an oxoglutaric acid and UDP-4-amino-4-deoxy-beta-L-arabinopyranose The latter compound interacts with a N10-formyl-tetrahydrofolate through a bifunctional polymyxin resistance protein ArnA, resulting in a tetrahydrofolate, a hydrogen ion and a UDP-4-deoxy-4-formamido-beta-L-arabinopyranose, which in turn reacts with a product of the methylerythritol phosphate and polysoprenoid biosynthesis pathway, di-trans,octa-cis-undecaprenyl phosphate to produce a 4-deoxy-4-formamido-alpha-L-arabinopyranosyl ditrans, octacis-undecaprenyl phosphate.
The compound 4-deoxy-4-formamido-alpha-L-arabinopyranosyl ditrans, octacis-undecaprenyl phosphate hypothetically reacts with water and results in the release of a formic acid and 4-amino-4-deoxy-α-L-arabinopyranosyl ditrans,octacis-undecaprenyl phosphate which in turn reacts with a KDO2-lipid A through a 4-amino-4-deoxy-L-arabinose transferase resulting in the release of a di-trans,octa-cis-undecaprenyl phosphate and a L-Ara4N-modified KDO2-Lipid APW002052MetabolicSpecdb::CMs1084246Specdb::MsMs23276Specdb::MsMs23277Specdb::MsMs23278Specdb::MsMs30074Specdb::MsMs30075Specdb::MsMs30076C16154Bifunctional polymyxin resistance protein ArnAP77398ARNA_ECOLIarnAhttp://ecmdb.ca/proteins/P77398.xmlUndecaprenyl-phosphate 4-deoxy-4-formamido-L-arabinose transferaseP77757ARNC_ECOLIarnChttp://ecmdb.ca/proteins/P77757.xmlN10-Formyl-THF + 4-Amino-4-deoxy-L-arabinose > Tetrahydrofolic acid + UDP-4-Deoxy-4-formamido-beta-L-arabinoseUDP-4-Deoxy-4-formamido-beta-L-arabinose + di-trans,octa-cis-undecaprenyl phosphate > Uridine 5'-diphosphate + 4-deoxy-4-formamido-alpha-L-arabinose di-trans,octa-cis-undecaprenyl phosphateUridine 5''-diphospho-{beta}-4-deoxy-4-amino-L-arabinose + an N10-formyl-tetrahydrofolate + N10-Formyl-THF > UDP-4-Deoxy-4-formamido-beta-L-arabinose + Hydrogen ion + a tetrahydrofolate + Tetrahydrofolic acidPW_R003358UDP-4-Deoxy-4-formamido-beta-L-arabinose + di-trans,octa-cis-undecaprenyl phosphate > Uridine 5'-diphosphate + 4-deoxy-4-formamido-α-L-arabinopyranosyl ditrans,octacis-undecaprenyl phosphatePW_R003359