Browsing Pathways

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism (Wikipedia). Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). Third, the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (PA or 1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. PA is then transferred to the inner mitochondrial membrane to continue cardiolipin synthesis. Fourth, magnesium-dependent phosphatidate cytidylyltransferase catalyzes the conversion of PA into CDP-diacylglycerol. Fifth, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase synthesizes phosphatidylglycerophosphate (PGP). Sixth, phosphatidylglycerophosphatase and protein-tyrosine phosphatase dephosphorylates PGP to form phosphatidylglycerol (PG). Last, cardiolipin synthase catalyzes the synthesis of cardiolipin by transferring a phosphatidyl group from a second CDP-diacylglycerol to PG. It requires a divalent metal cation cofactor.

Lipopolysaccharide (LPS) is a major component of outer membrane which is consisted of lipid A-core (oligosaccharide) on both inner and outer region and O-antigen (known as distal repeating unit with four sugars: N-acetylglucosamine, glucose, rhamnose and galactose). O-antigen is part of three domains of LPS, which is attached to lipid A-core; however, O-antigen and lipid A-core are synthesized separately. In this pathway, synthesis of three of O-antigen sugars is demonstrated. UDP-α-D-galactose is converted to UDP-D-Galacto-1,4-furanose by facilitation of UDP-galactopyranose mutase. dTTP glucose-1-phosphate is derivatized to dTDP-rhamnose. Fructose-6-phosphate gains an amino group, incorporates an acetate moiety and then acquires a nucleoside diphosphate resulting in UDP-N-acetyl-D-glucosamine.

Lipopolysaccharide (LPS) is a major component of outer membrane which is consisted of lipid A-core (oligosaccharide) on both inner and outer region and O-antigen (known as distal repeating unit with four sugars: N-acetylglucosamine, glucose, rhamnose and galactose). O-antigen is part of three domains of LPS, which is attached to lipid A-core; however, O-antigen and lipid A-core are synthesized separately. In this pathway, synthesis of three of O-antigen sugars is demonstrated. UDP-α-D-galactose is converted to UDP-D-Galacto-1,4-furanose by facilitation of UDP-galactopyranose mutase. dTTP glucose-1-phosphate is derivatized to dTDP-rhamnose. Fructose-6-phosphate gains an amino group, incorporates an acetate moiety and then acquires a nucleoside diphosphate resulting in UDP-N-acetyl-D-glucosamine.

Lipopolysaccharide (LPS) is a major component of outer membrane which is consisted of lipid A-core (oligosaccharide) on both inner and outer region and O-antigen (known as distal repeating unit with four sugars: N-acetylglucosamine, glucose, rhamnose and galactose). O-antigen is part of three domains of LPS, which is attached to lipid A-core; however, O-antigen and lipid A-core are synthesized separately. In this pathway, synthesis of three of O-antigen sugars is demonstrated. UDP-α-D-galactose is converted to UDP-D-Galacto-1,4-furanose by facilitation of UDP-galactopyranose mutase. dTTP glucose-1-phosphate is derivatized to dTDP-rhamnose. Fructose-6-phosphate gains an amino group, incorporates an acetate moiety and then acquires a nucleoside diphosphate resulting in UDP-N-acetyl-D-glucosamine.

Rhamnolipids (RL) consist of a fatty acyl moiety composed of a 3-(3-hydroxyalkanoyloxy)alkaloid acid (HAA) and a sugar moiety composed of one or two rhamnose sugars. Rhamnolipids function as surfactants and virulence factors and are involved in biofilm formation and cell motility. The rhamnose sugar component is produced via the dTDP-L-rhamnose biosynthetic pathway which forms dTDP-L-rhamnose from glucose 6-phosphate (G6P) in five steps. First, glucose 6-phosphate is converted into glucose 1-phosphate (G1P) via the enzyme phosphoglucomutase (AlgC). Second, glucose 1-phosphate is converted into dTDP-D-glucose via the enzyme glucose-1-phosphate thymidylyltransferase (RmlA). Third, dTDP-D-glucose is converted into dTDP-4-dehydro-6-deoxy-D-glucose via the enzyme dTDP-glucose 4,6-dehydratase (RmlB). Fourth, dTDP-4-dehydro-6-deoxy-D-glucose is converted into dTDP-4-dehydro-L-rhamnose via the enzyme dTDP-4-dehydrorhamnose 3,5-epimerase (RmlC). Fifth, dTDP-4-dehydro-L-rhamnose is converted into dTDP-L-rhamnose via the enzyme dTDP-4-dehydrorhamnose reductase (RmlD). The HAA component is synthesized from 3-hydroxyacyl-[acyl-carrier protein] diverted from fatty acid biosynthesis via the enzyme 3-(3-hydroxydecanoyloxy)decanoate synthase (RhIA). The final step in rhamnolipid biosynthesis is the formation of the glycosidic link between the rhamnose sugar component and the HAA component. This is accomplished by two rhamnosyltransferases (RhlB and RhlC) which catalyze sequential glycosyl transfer reactions to first form mono-rhamnolipids (via RhIB) and then di-rhamnolipids (via RhIC). RHlA, RHlB, and RHlC are associated with the inner membrane.

Rhamnolipids (RL) consist of a fatty acyl moiety composed of a 3-(3-hydroxyalkanoyloxy)alkaloid acid (HAA) and a sugar moiety composed of one or two rhamnose sugars. Rhamnolipids function as surfactants and virulence factors and are involved in biofilm formation and cell motility. The rhamnose sugar component is produced via the dTDP-L-rhamnose biosynthetic pathway which forms dTDP-L-rhamnose from glucose 6-phosphate (G6P) in five steps. First, glucose 6-phosphate is converted into glucose 1-phosphate (G1P) via the enzyme phosphoglucomutase (AlgC). Second, glucose 1-phosphate is converted into dTDP-D-glucose via the enzyme glucose-1-phosphate thymidylyltransferase (RmlA). Third, dTDP-D-glucose is converted into dTDP-4-dehydro-6-deoxy-D-glucose via the enzyme dTDP-glucose 4,6-dehydratase (RmlB). Fourth, dTDP-4-dehydro-6-deoxy-D-glucose is converted into dTDP-4-dehydro-L-rhamnose via the enzyme dTDP-4-dehydrorhamnose 3,5-epimerase (RmlC). Fifth, dTDP-4-dehydro-L-rhamnose is converted into dTDP-L-rhamnose via the enzyme dTDP-4-dehydrorhamnose reductase (RmlD). The HAA component is synthesized from 3-hydroxyacyl-[acyl-carrier protein] diverted from fatty acid biosynthesis via the enzyme 3-(3-hydroxydecanoyloxy)decanoate synthase (RhIA). The final step in rhamnolipid biosynthesis is the formation of the glycosidic link between the rhamnose sugar component and the HAA component. This is accomplished by two rhamnosyltransferases (RhlB and RhlC) which catalyze sequential glycosyl transfer reactions to first form mono-rhamnolipids (via RhIB) and then di-rhamnolipids (via RhIC). RHlA, RHlB, and RHlC are associated with the inner membrane.

L-threonine is degrade into methylglyoxal (pyruvaldehyde) by first reacting with a NDA dependent threonine dehydrogenase resulting in the release of a hydrogen ion, an NADH and a 2-amino-3-oxobutanoate. The latter compound reacts spontaneously with a hydrogen ion resulting in the release of a carbon dioxide and a aminoacetone. The aminoacetone in turn reacts with an oxygen and a water molecule through an aminoacetone oxidase resulting in the release of a hydrogen peroxide, ammonium and a methylglyoxal which can then be incorporated in the methylglyoxal degradation pathways.

Guanosine can be converted into guanine through a phosphate driven guanosine phosphorylase resulting in the release of an alpha-D-ribose 1 phosphate and a guanine. This compound in turn reacts with a PRPP through a guanine phosphoribosyltransferase resulting in the release of a pyrophosphate and a GMP. Guanosine can also react with and ATP driven guanosine kinase resulting in the release of an ADP, s hydrogen ion and a GMP

This pathway is a compilation of Escherichia coli inner membrane transport complexes that transport compounds from the periplasmic space into the cytosol. Many compound classes are carried by these inner membrane transport complexes including sugars, amino acids, and lipids.

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.