Browsing Pathways

ADP-L-glycero-β-D-manno-heptose is a precursor for the inner core lipopolysaccharide (LPS), which is the outer membrane of Gram-negative bacteria. LPS is consisted of lipid A, a core oligosaccharide, and an O-specific polysaccharide (O antigen). This biosynthesis pathway starts with catalyzation of D-sedoheptulose 7-phosphate that produced from pentose phosphate pathway to form D-glycero-D-manno-heptose 7-phosphate by lysophospholipid acyltransferase. D-glycero-D-manno-heptose 7-phosphate later undergoes catalyze to form D-glycero-β-D-manno-heptose 1,7-bisphosphate by fused heptose 7-phosphate kinase (also known as heptose 1-phosphate adenyltransferase) that powered by ATP. D-glycero-β-D-manno-heptose 1,7-bisphosphate will go through hydrolysis by D,D-heptose 1,7-bisphosphate phosphatase to form D-glycero-β-D-manno-heptose 1-phosphate and a phosphate. D-glycero-β-D-manno-heptose 1-phosphate will form ADP-D-Glycero-D-manno-heptose and diphosphate, and eventually ADP-D-Glycero-D-manno-heptose will be biotransformed to ADP-L-glycero-β-D-manno-heptose as the end product of this pathway by ADP-L-glycero-D-mannoheptose-6-epimerase.

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.

Sedoheptulose bisphospate bypass pathway demonstrates a series of reaction that form D-Erythrose 4-phosphate for pentose phosphate pathway and glycerone phosphate for glycolysis and pyruvate dehydrogenase pathway. D-Sedoheptulose 7-phosphate is obtained from pentose phosphate pathway, which later converted to sedoheptulose 1,7-bisphosphate via 6-phosphofructokinase-1. Fructose-bisphosphate aldolase class 2 catalyzes sedoheptulose 1,7-bisphosphate to form D-Erythrose 4-phosphate and pyruvate dehydrogenase.

The regulation of the operon metBL. The operon is repressed by metJ (Met repressor) when its bound with SAM (S-adenosylmethionine). SAM is required for metJ to bind to the promoter. Therefore, the absence of SAM activates the operon because metJ can no longer bind to the promoter. SAM is a product of the methionine pathway. The operon has two products: metB (Cystathionine gamma-synthase), metL (Bifunctional aspartokinase/homoserine dehydrogenase 2). Both of these products are enzymes used in the methionine biosynthesis. MetB catalyzes the reaction O-succinyl-L-homoserine to L,L-cystathionine. MetL catalyzes two different reactions in the methionine pathway. They include the first step (L-aspartate to 4-phospho-L-aspartate) and the third step (L-aspartate 4-semialdehyde to L-homoserine) in the creation of L-homoserine from L-aspartate.

Phospholipids are membrane components in E. coli. The major phospholipids of E. coli are phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin. All phospholipids contain sn-glycerol-3-phosphate esterified with fatty acids at the sn-1 and sn-2 positions. The reaction starts from a glycerone phosphate (dihydroxyacetone phosphate) produced in glycolysis. The glycerone phosphate is transformed into an sn-glycerol 3-phosphate (glycerol 3 phosphate) by NADPH-driven glycerol-3-phosphate dehydrogenase. sn-Glycerol 3-phosphate is transformed to a 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid). This can be achieved by an sn-glycerol-3-phosphate acyltransferase that interacts either with a long-chain acyl-CoA or with an acyl-[acp]. The 1-acyl-sn-glycerol 3-phosphate is transformed into a 1,2-diacyl-sn-glycerol 3-phosphate (phosphatidic acid) through a 1-acylglycerol-3-phosphate O-acyltransferase. This compound is then converted into a CPD-diacylglycerol through a CTP phosphatidate cytididyltransferase. CPD-diacylglycerol can be transformed either into an L-1-phosphatidylserine or an L-1-phosphatidylglycerol-phosphate through a phosphatidylserine synthase or a phosphatidylglycerophosphate synthase, respectively. The L-1-phosphatidylserine transforms into L-1-phosphatidylethanolamine through a phosphatidylserine decarboxylase. On the other hand, L-1-phosphatidylglycerol-phosphate gets transformed into an L-1-phosphatidyl-glycerol through a phosphatidylglycerophosphatase. These 2 products combine to produce a cardiolipin and an ethanolamine. The L-1 phosphatidyl-glycerol can also interact with cardiolipin synthase resulting in a glycerol and a cardiolipin.

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.

The 5-phosphoribosyl 1-pyrophosphate (PRPP) effector pathway is a central metabolic route responsible for the de novo biosynthesis of purine nucleotides (AMP and GMP), which are essential for DNA, RNA, energy metabolism, and cellular signaling. This pathway is tightly regulated by PurR, a purine-responsive transcriptional repressor. PurR senses intracellular purine levels and represses the expression of purine biosynthesis genes when purines are abundant. When purine levels are low, PurR repression is relieved, allowing the transcription of genes necessary for building purines from basic metabolic precursors, with PRPP as the starting substrate. In response to a signal of excess adenine, represses the transcription of the pur operon, which encodes enzymes of the purine biosynthetic pathway. Key genes in the PurR regulog include: Core de novo purine biosynthesis genes: purF – Encodes amidophosphoribosyltransferase, catalyzing the first committed step of the pathway: the conversion of PRPP to phosphoribosylamine. purD – Encodes GAR synthetase, catalyzing the formation of glycinamide ribonucleotide (GAR). purN – Encodes GAR transformylase, which converts GAR to formyl-GAR. purL, purQ, purS – These form a multi-subunit enzyme complex (FGAM synthetase) that converts formyl-GAR to formylglycinamidine ribonucleotide (FGAM). purM – Encodes AIR synthetase, catalyzing the formation of aminoimidazole ribonucleotide (AIR). purE – Encodes N5-CAIR mutase, converting AIR into carboxyaminoimidazole ribonucleotide (CAIR). purK – Encodes N5-CAIR synthetase, functioning upstream of purE in CAIR formation. purC – Encodes SAICAR synthetase, catalyzing the conversion of CAIR to SAICAR. purB – Encodes adenylosuccinate lyase, which participates in two reactions: conversion of SAICAR to AICAR and of adenylosuccinate to AMP. purH – Encodes a bifunctional enzyme with AICAR transformylase and IMP cyclohydrolase activities, catalyzing the final steps in IMP (inosine monophosphate) synthesis. Downstream conversion of IMP: purA – Encodes adenylosuccinate synthetase, converting IMP to AMP. guaC – Encodes GMP reductase, contributing to purine interconversion and balance between AMP and GMP pools. Accessory genes: fhs – Encodes formyltetrahydrofolate synthetase, which generates the one-carbon donor (10-formyl-THF) required for GAR and AICAR formylation steps. LGG_02640 – Likely encodes a gene co-expressed with purine biosynthetic genes, possibly involved in folate metabolism or regulation.

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.

The regulation of the dgoRKADT operon. The operon is inhibited by dgoR (Galactonate operon transcriptional repressor) and activated by galactonate. DgoR inhibits the operon by binding to two closely spaced inverted repeats in the cis-acting element, which overlap with the D-galactonate responsive dgo promoter. When galactonate is present, it binds to dgoR, causing conformational changes resulting in dgoR releasing the promoter. The operon has five products: dgoR, dgoK (2-dehydro-3-deoxygalactonokinase), dgoA (2-dehydro-3-deoxy-6-phosphogalactonate aldolase), dgoD (D-galactonate dehydratase) and dgoT (D-galactonate transporter). DgoK, dgoA and dgoD are enzymes used in the utilization of galactonate (galactonate to pyruvate and D-glyceraidehyde-3-phosphate). Galactonate is brought into the cell by dgoT transporter. DgoD is used to turn galactonate to 2-dehydro-3-deoxy-D-galactonate. DgoK is used to turn 2-dehydro-3-deoxy-D-galactonate to 2-dehydro-3-deoxy-D-galactonate-6-phosphate. DgoA is used to turn 2-dehydro-3-deoxy-D-galactonate-6-phosphate to pyruvate and D-glyceraidehyde-3-phosphate.

Glycerol metabolism starts with glycerol is introduced into the cytoplasm through a glycerol channel GlpF Glycerol is then phosphorylated through an ATP mediated glycerol kinase resulting in a Glycerol 3-phosphate. This compound can also be obtained through a glycerophosphodiester reacting with water through a glycerophosphoryl diester phosphodiesterase or it can also be introduced into the cytoplasm through a glycerol-3-phosphate:phosphate antiporter. Glycerol 3-phosphate is then metabolized into a dihydroxyacetone phosphate in both aerobic or anaerobic conditions. In anaerobic conditions the metabolism is done through the reaction of glycerol 3-phosphate with a menaquinone mediated by a glycerol-3-phosphate dehydrogenase protein complex. In aerobic conditions, the metabolism is done through the reaction of glycerol 3-phosphate with ubiquinone mediated by a glycerol-3-phosphate dehydrogenase [NAD(P]+]. Dihydroxyacetone phosphate is then introduced into the fructose metabolism by turning a dihydroxyacetone into an isomer through a triosephosphate isomerase resulting in a D-glyceraldehyde 3-phosphate which in turn reacts with a phosphate through a NAD dependent Glyceraldehyde 3-phosphate dehydrogenase resulting in a glyceric acid 1,3-biphosphate. This compound is desphosphorylated by a phosphoglycerate kinase resulting in a 3-phosphoglyceric acid.This compound in turn can either react with a 2,3-bisphosphoglycerate-independent phosphoglycerate mutase or a 2,3-bisphosphoglycerate-independent phosphoglycerate mutase resulting in a 2-phospho-D-glyceric acid. This compound interacts with an enolase resulting in a phosphoenolpyruvic acid and water. Phosphoenolpyruvic acid can react either through a AMP driven phosphoenoylpyruvate synthase or a ADP driven pyruvate kinase protein complex resulting in a pyruvic acid. Pyruvic acid reacts with CoA through a NAD driven pyruvate dehydrogenase complex resulting in a carbon dioxide and a Acetyl-CoA which gets incorporated into the TCA cycle pathway.