Pathways

The pentose phosphate pathway—also referred to in the literature as the phosphogluconate pathway, the hexose monophosphate shunt, or the pentose phosphate shunt—is involved in the generation of NADPH as well as pentose sugars. Of the total cytoplasmic NADPH used in biosynthetic reactions, a significant proportion of it is generated through the pentose phosphate pathway. Ribose 5-phosphate is also another essential product generated by this pathway which is employed in nucleotide synthesis. The pentose phosphate pathway is also involved in the digestive process as the products of nucleic acid catabolism can be metabolized through the pathway (pentose sugars are usually yielded in the breakdown) while the carbon backbones of dietary carbohydrates can be converted into glycolytic/gluconeogenic intermediates. The pentose phosphate pathway is interconnected to the glycolysis pathway through the shared use of three intermediates: glucose 6-phosphate, glyceraldehyde 3-phosphate, and fructose 6-phosphate. The pathway can be described as eight distinct reactions (see below) and is separated into an oxidative phase and a non-oxidative phase. Reactions 1-3 form the oxidative phase and generate NADPH and pentose 5-phosphate. Reactions 4-8 form the non-oxidative phase and converts pentose 5-phosphate into other pentose sugars such as ribose 5-phosphate, but generates no NADPH. The eight reactions are as follows: reaction 1 where glucose-6-phosphate 1-dehydrogenase converts glucose 6-phosphate into D-glucono-1,5-lactone 6-phosphate with NADPH formation; reaction 2 where 6-phosphogluconolactonase converts D-glucono-1,5-lactone 6-phosphate into 6-phospho-D-gluconate;reaction 3 where 6-phosophogluconate dehydrogenase converts 6-phospho-D-gluconate into ribulose 5-phosphate with NADPH formation; reaction 4 where ribulose-phosphate 3-epimerase converts ribulose 5-phosphate into xylulose 5-phosphate; reaction 5 where ribose-5-phosphate isomerase converts ribulose 5-phosphate into ribose 5-phosphate; reaction 6 where transketolase rearranges ribose 5-phosphate and xylulose 5-phosphate to form sedoheptulose 7-phosphate and glyceraldehyde 3-phosphate; reaction 7 where transaldolase rearranges of sedoheptulose 7-phosphate and glyceraldehyde 3-phosphate to form erythrose 4-phosphate and fructose 6-phosphate; and reaction 8 where transkelotase rearranges of xylulose 5-phosphate and erythrose 4-phosphate to form glyceraldehyde 3-phosphate and fructose-6-phosphate.

The pentose phosphate pathway—also referred to in the literature as the phosphogluconate pathway, the hexose monophosphate shunt, or the pentose phosphate shunt—is involved in the generation of NADPH as well as pentose sugars. Of the total cytoplasmic NADPH used in biosynthetic reactions, a significant proportion of it is generated through the pentose phosphate pathway. Ribose 5-phosphate is also another essential product generated by this pathway which is employed in nucleotide synthesis. The pentose phosphate pathway is also involved in the digestive process as the products of nucleic acid catabolism can be metabolized through the pathway (pentose sugars are usually yielded in the breakdown) while the carbon backbones of dietary carbohydrates can be converted into glycolytic/gluconeogenic intermediates. The pentose phosphate pathway is interconnected to the glycolysis pathway through the shared use of three intermediates: glucose 6-phosphate, glyceraldehyde 3-phosphate, and fructose 6-phosphate. The pathway can be described as eight distinct reactions (see below) and is separated into an oxidative phase and a non-oxidative phase. Reactions 1-3 form the oxidative phase and generate NADPH and pentose 5-phosphate. Reactions 4-8 form the non-oxidative phase and converts pentose 5-phosphate into other pentose sugars such as ribose 5-phosphate, but generates no NADPH. The eight reactions are as follows: reaction 1 where glucose-6-phosphate 1-dehydrogenase converts glucose 6-phosphate into D-glucono-1,5-lactone 6-phosphate with NADPH formation; reaction 2 where 6-phosphogluconolactonase converts D-glucono-1,5-lactone 6-phosphate into 6-phospho-D-gluconate;reaction 3 where 6-phosophogluconate dehydrogenase converts 6-phospho-D-gluconate into ribulose 5-phosphate with NADPH formation; reaction 4 where ribulose-phosphate 3-epimerase converts ribulose 5-phosphate into xylulose 5-phosphate; reaction 5 where ribose-5-phosphate isomerase converts ribulose 5-phosphate into ribose 5-phosphate; reaction 6 where transketolase rearranges ribose 5-phosphate and xylulose 5-phosphate to form sedoheptulose 7-phosphate and glyceraldehyde 3-phosphate; reaction 7 where transaldolase rearranges of sedoheptulose 7-phosphate and glyceraldehyde 3-phosphate to form erythrose 4-phosphate and fructose 6-phosphate; and reaction 8 where transkelotase rearranges of xylulose 5-phosphate and erythrose 4-phosphate to form glyceraldehyde 3-phosphate and fructose-6-phosphate.

Pentostatin is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Pentostatin passes through the liver and is then excreted from the body mainly through the kidney.

Peptidoglycan is a net-like polymer which surrounds the cytoplasmic membrane of most bacteria and functions to maintain cell shape and prevent rupture due to the internal turgor.In E. coli K-12, the peptidoglycan consists of glycan strands of alternating subunits of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) which are cross-linked by short peptides. The pathway for constructing this net involves two cell compartments: cytoplasm and periplasmic space. The pathway starts with a beta-D-fructofuranose going through a mannose PTS permease, phosphorylating the compund and producing a beta-D-fructofuranose 6 phosphate. This compound can be obtained from the glycolysis and pyruvate dehydrogenase or from an isomerization reaction of Beta-D-glucose 6-phosphate through a glucose-6-phosphate isomerase.The compound Beta-D-fructofuranose 6 phosphate and L-Glutamine react with a glucosamine fructose-6-phosphate aminotransferase, thus producing a glucosamine 6-phosphate and a l-glutamic acid. The glucosamine 6-phosphate interacts with phosphoglucosamine mutase in a reversible reaction producing glucosamine-1P. Glucosamine-1p and acetyl coa undergo acetylation throuhg a bifunctional protein glmU releasing Coa and a hydrogen ion and producing a N-acetyl-glucosamine 1-phosphate. Glmu, being a bifunctional protein, follows catalyze the interaction of N-acetyl-glucosamine 1-phosphate, hydrogen ion and UTP into UDP-N-acetylglucosamine and pyrophosphate. UDP-N-acetylglucosamine then interacts with phosphoenolpyruvic acid and a UDP-N acetylglucosamine 1- carboxyvinyltransferase realeasing a phosphate and the compound UDP-N-acetyl-alpha-D-glucosamine-enolpyruvate. This compound undergoes a NADPH dependent reduction producing a UDP-N-acetyl-alpha-D-muramate through a UDP-N-acetylenolpyruvoylglucosamine reductase. UDP-N-acetyl-alpha-D-muramate and L-alanine react in an ATP-mediated ligation through a UDP-N-acetylmuramate-alanine ligase releasing an ADP, hydrogen ion, a phosphate and a UDP-N-acetylmuramoyl-L-alanine. This compound interacts with D-glutamic acid and ATP through UDP-N-acetylmuramoylalanine-D-glutamate ligase releasing ADP, A phosphate and UDP-N-acetylmuramoyl-L-alanyl-D-glutamate. The latter compound then interacts with meso-diaminopimelate in an ATP mediated ligation through a UDP-N-acetylmuramoylalanine-D-glutamate-2,6-diaminopimelate ligase resulting in ADP, phosphate, hydrogen ion and UDP-N-Acetylmuramoyl-L-alanyl-D-gamma-glutamyl-meso-2,6-diaminopimelate. This compound in turn with D-alanyl-D-alanine react in an ATP-mediated ligation through UDP-N-Acetylmuramoyl-tripeptide-D-alanyl-D-alanine ligase to produce UDP-N-acetyl-alpha-D-muramoyl-L-alanyl-gama-D-glutamyl-meso-2,6-diaminopimeloyl-Dalanyl-D-alanine and hydrogen ion, ADP, phosphate. UDP-N-acetyl-alpha-D-muramoyl-L-alanyl-gama-D-glutamyl-meso-2,6-diaminopimeloyl-Dalanyl-D-alanine interacts with di-trans,octa-cis-undecaprenyl phosphate through a phospho-N-acetylmuramoyl-pentapeptide-transferase, resulting in UMP and N-Acetylmuramoyl-L-alanyl-D-glutamyl-meso-2,6-diaminopimelyl-D-alanyl-D-alanine-diphosphoundecaprenol which in turn reacts with a UDP-N-acetylglucosamine through a N-acetylglucosaminyl transferase to produce a hydrogen, UDP and Undecaprenyl-diphospho-N-acetylmuramoyl-(N-acetylglucosamine)-L-alanyl-D-glutaminyl-meso-2,6-diaminopimeloyl-D-alanyl-D-alanine. This compound ends the cytoplasmic part of the pathway. Undecaprenyl-diphospho-N-acetylmuramoyl-(N-acetylglucosamine)-L-alanyl-D-glutaminyl-meso-2,6-diaminopimeloyl-D-alanyl-D-alanine is transported through a lipi II flippase. Once in the periplasmic space, the compound reacts with a penicillin binding protein 1A prodducing a peptidoglycan dimer, a hydrogen ion, and UDP. The peptidoglycan dimer then reacts with a penicillin binding protein 1B producing a peptidoglycan with D,D, cross-links and a D-alanine.

Peptidoglycan is a net-like polymer which surrounds the cytoplasmic membrane of most bacteria and functions to maintain cell shape and prevent rupture due to the internal turgor. In E. coli K-12, the peptidoglycan consists of glycan strands of alternating subunits of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) which are cross-linked by short peptides. The pathway for constructing this net involves two cell compartments: cytoplasm and periplasmic space. The pathway starts with a beta-D-fructofuranose going through a mannose PTS permease, phosphorylating the compound and producing a beta-D-fructofuranose 6 phosphate. This compound can be obtained from the glycolysis and pyruvate dehydrogenase or from an isomerization reaction of Beta-D-glucose 6-phosphate through a glucose-6-phosphate isomerase. The compound Beta-D-fructofuranose 6 phosphate and L-Glutamine react with a glucosamine fructose-6-phosphate aminotransferase, thus producing a glucosamine 6-phosphate and a l-glutamic acid. The glucosamine 6-phosphate interacts with phosphoglucosamine mutase in a reversible reaction producing glucosamine-1P. Glucosamine-1p and acetyl-CoA undergo acetylation through a bifunctional protein glmU releasing Coa and a hydrogen ion and producing a N-acetyl-glucosamine 1-phosphate. Glmu, being a bifunctional protein catalyzes the interaction of N-acetyl-glucosamine 1-phosphate, hydrogen ion and UTP into UDP-N-acetylglucosamine and pyrophosphate. UDP-N-acetylglucosamine then interacts with phosphoenolpyruvic acid and a UDP-N acetylglucosamine 1- carboxyvinyltransferase releasing a phosphate and the compound UDP-N-acetyl-alpha-D-glucosamine-enolpyruvate. The latter undergoes a NADPH dependent reduction producing a UDP-N-acetyl-alpha-D-muramate catalyzed by a UDP-N-acetylenolpyruvoylglucosamine reductase. UDP-N-acetyl-alpha-D-muramate and L-alanine react in an ATP-mediated ligation through a UDP-N-acetylmuramate-alanine ligase releasing an ADP, hydrogen ion, phosphate and a UDP-N-acetylmuramoyl-L-alanine. Next, UDP-N-acetylmuramoylalanine-D-glutamate ligase catalyzes an ATP, D-glutamic acid and UDP-N-acetylmuramoyl-L-alanine releasing ADP, phosphate and UDP-N-acetylmuramoyl-L-alanyl-D-glutamate. The latter product then interacts with meso-diaminopimelate in an ATP mediated ligation through a UDP-N-acetylmuramoylalanine-D-glutamate-2,6-diaminopimelate ligase resulting in ADP, phosphate, hydrogen ion and UDP-N-Acetylmuramoyl-L-alanyl-D-gamma-glutamyl-meso-2,6-diaminopimelate. This compound in turn with D-alanyl-D-alanine react in an ATP-mediated ligation through UDP-N-Acetylmuramoyl-tripeptide-D-alanyl-D-alanine ligase to produce UDP-N-acetyl-alpha-D-muramoyl-L-alanyl-gama-D-glutamyl-meso-2,6-diaminopimeloyl-Dalanyl-D-alanine and hydrogen ion, ADP, phosphate. UDP-N-acetyl-alpha-D-muramoyl-L-alanyl-gama-D-glutamyl-meso-2,6-diaminopimeloyl-Dalanyl-D-alanine interacts with di-trans,octa-cis-undecaprenyl phosphate through a phospho-N-acetylmuramoyl-pentapeptide-transferase, resulting in UMP and Undecaprenyl-diphospho-N-acetylmuramoyl-L-alanyl-D-glutamyl-meso-2,6-diaminopimeloyl-D-alanyl-D-alanine which in turn reacts with a UDP-N-acetylglucosamine through a N-acetylglucosaminyl transferase to produce a hydrogen, UDP and ditrans,octacis-undecaprenyldiphospho-N-acetyl-(N-acetylglucosaminyl)muramoyl-L-alanyl-gamma-D-glutamyl-meso-2,6-diaminopimeloyl-D-alanyl-D-alanine. This compound ends the cytoplasmic part of the pathway. ditrans,octacis-undecaprenyldiphospho-N-acetyl-(N-acetylglucosaminyl)muramoyl-L-alanyl-gamma-D-glutamyl-meso-2,6-diaminopimeloyl-D-alanyl-D-alanine is transported through a lipi II flippase. Once in the periplasmic space, the compound reacts with a penicillin binding protein 1A prodducing a peptidoglycan dimer, a hydrogen ion, and UDP. The peptidoglycan dimer then reacts with a penicillin binding protein 1B producing a peptidoglycan with D,D, cross-links and a D-alanine.

Peramivir, also known as Rapivab, is an antiviral agent used to treat acute uncomplicated influenza A and B. Being a specific influenza virus neuraminidase inhibitor, peramivir works by preventing new viruses from emerging out of infected host cells. Viral Neuraminidase helps viruses to be released from the plasma membrane of the host cell after budding by cleaving terminal sialic acid residues from glycan structures on the surface of the infected cell. The active site of the neuraminidase enzyme is highly conserved, making it a good structure to inhibit. By inhibiting the NA catalytic site, peramivir causes viruses to aggregate and fail to be released from the cell surface. This drug has a low bioavailability when taken orally, so the only available formulation is the injectable intravenous.