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Glycolysis and Cellular Respiration

Introduction

All cells require continuous supply of energy for various activities like basal metabolic activities, replenishment of worn out biomolecules & cellular components, organelles’ trafficking, active transport, homeostasis, etc. Adenosine triphosphate (ATP) is the most feasible means of intracellular energy expenditure used for these metabolic pathways, thus it’s also known as ‘energy currency’ of the cell. The process of oxidative breakdown of energy rich molecules (sugars, amino acids, fat, etc.) by the cell to produce cellular energy (ATP) is called cellular respiration. A cellular respiration pathway requiring oxygen as the terminal electron acceptor is called aerobic (cellular) respiration. The other cellular respiration pathway occurring in absence of oxygen as the terminal electron acceptor is called anaerobic (cellular) respiration.

In case of aerobic respiration, hallmarked by the use of O2 as the terminal electron acceptor, CO2 and H2O form the end products of glucose oxidation through sequential events of three distinct processes- glycolysis, tricarboxylic acid cycle (TCA) and electron transport chain coupled oxidative phosphorylation. Glycolysis occurs in cytoplasm whereas TCA and electron transport chain coupled oxidative phosphorylation occur in the mitochondria. Plant cells also require energy for their survival. Though the plant cells containing the photosynthetic apparatus synthesize ATP during photosynthesis, it may not meet up the actual requirement of energy all the time. To compensate energy demand, the photosynthesizing plant cells also oxidize glucose simultaneously to some extent during photosynthesis, too. Rest of the non-photosynthesizing cells totally depend on oxidation of glucose (photosynthetic product) for ATP need. So, all the plant cells, whether photosynthesizing or not, carry out cellular respiration. It’s not surprising that around 30-60 % of the total carbon fixed by a plant is used up during cellular respiration.

In case of anaerobic respiration, the electrons are taken up by NO3, Fe3+, Mn2+, SO42-, CO2, DMSO, or other inorganic and organic molecules depending on the metabolic pathway of that anaerobe.

Glycolysis or EMP (Embden–Meyerhof–Parnas) Pathway

The breakdown of glucose (and, other 6C carbohydrates) into two molecules of pyruvate is called glycolysis. All the enzymes required for this ten-step process are present in the cytoplasm. Being oxygen-independent pathway taking place in the cytosol, it occurs in almost all cellular organisms (aerobes and anaerobes) across the three domains of life. The pathways can be divided into ‘preparatory phase’ (steps 1-5) and ‘payoff phase’ (steps 6- 10). All the steps of glycolysis are summarized below.

Steps of Glycolysis starting from Glucose (Fischer projections)

Steps of Glycolysis starting from Glucose (Haworth projection)

The preparatory phase involves ATP investment in the two priming steps, step 1 (conversion of Glucose into Glucose 6-phosphate, G-6-P by hexokinase) and step 3 (conversion of Fructose 6-phosphate, F-6-P into Fructose 1,6-bisphoaphate, F 1,6-bisP by phosphofructokinase 1). The end of this phase is marked by splitting of the 6C This phase is fructose 1,6-bisphoaphate into glyceraldehyde 3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP). Under the physiological conditions of RBCs, the enzyme triose phosphate isomerase catalyzes the conversion of DHAP into G3P with an enthalpy (ΔG) value of 2.4 kJ/mol (the +ve sign of ΔG indicates a non-spontaneous reaction). However, the continuous consumption of G3P in further reactions of glycolysis shifts the equilibrium towards the formation of G3P. The net reaction of this phase can be written as-

            Glucose + 2 ATP → G3P + DHAP + 2 ADP + 2 Pi

Since DHAP is ultimately converted into G3P, the above reaction can be written in terms of G3P as follow-

            Glucose + 2 ATP → 2 G3P + 2 ADP + 2 Pi

The payoff phase involves formation of energy rich molecules NADH and ATP during the reactions sequentially forming pyruvate from G3P. Note that a single glucose molecule forms two molecules of G3P. And, all the reactions of this phase involve two molecules of their respective reactants and products for complete glycolysis of a single glucose molecule. Besides all other facts of metabolisms, glyceraldehyde 3-phosphate dehydrogenase is one of the few molecules that exhibit homotropic negative cooperativity towards binding of its NAD+. The net reaction of this phase can be written as-

            G3P + NAD+ + 2 ADP + 3 Pi → Pyruvate + 2 ATP + NADH + H+ + H2O

Accounting the stoichiometry of two G3P molecules from each glucose molecule, the above reaction can be multiplied by the stoichiometric coefficient of 2 to present the net reaction of the payoff phase for one glucose molecule as follows-

     2 G3P + 2 NAD+ + 4 ADP + 6 Pi → 2 Pyruvate + 4 ATP + 2 NADH + 2 H+ + 2 H2O

The net reaction of glycolysis can be written as the sum of the net reactions of preparatory and payoff phase for one glucose molecule as shown below. Note the appearance of thee inorganic phosphate molecules (Pi) on the reactant side instead of 2 Pi molecules generally found in many texts.

Entry of Fructose into the Glycolytic pathway

The entry of different sugar molecules into the glycolytic path may take different routes deepening on the cell types. Even different cell types in animals may exhibit difference in the entry pathway. For the simplicity of explanation, this chapter presents the example of fructose only in the context of human body. After absorption in the body, the dietary fructose is primarily catabolized in the liver. In hepatocytes, the catalysis of fructose via glycolysis is mediated by three enzymes- fructokinase (= ketohexokinase), fructose bisphosphate aldolase B (= aldolase B) and ATP-dependent dihydroxyacetone kinase (also known as triokinase and triose kinase). Adipocytes lack the enzyme fructokinase, but have hexokinase. So, in adipocytes, fructose is first converted into fructose-6-phophate, then enters into the glycolytic pathway as usual. 

Fructose may enter the glycolytic pathway by forming either fructose 1-phosphate (F-1-P) or the usual fructose 6-phosphate (F-6-P) intermediate. Adipocytes follow the more usual path by converting fructose into fructose 6-phophate- the normal intermediate of glycolysis. In the intestine, liver and kidney fructose is first converted into fructose 1-phosphate. The complete glycolytic cycle for fructose in the adipocytes and hepatocytes is shown in the picture below. Once formation of glyceraldehyde 3-phosphate, both the pathways take the same pathway further for the payoff phase. The pathway of entry of fructose into the glycolytic pathway in both the adipocyte and hepatocyte is shown below-

Entry of Fructose into the Glycolytic Pathway 

The net reaction for glycolysis for glucose and fructose in adipocytes and fructose in hepatocytes are summarized below. Note the common features of all these paths, the end products in all the three cases remain the same.

Net Reactions of Glycolysis for Glucose and Fructose

The Fates of Pyruvate

Pyruvate is the end product of glycolysis- a ubiquitous catabolic process acting as the primary energy producing pathway during cellular respiration in all the three domains of life. Owing to the myriad variations in cellular and metabolomics architecture, pyruvate may participate different metabolic routes in different cell types and their respective physiological conditions. During cellular respiration, it can have only two fates- to enter either aerobic or anaerobic respiration. Its entry to the aerobic respiration via citric acid cycle in mitochondria yields CO2, H2O and ATP as the end product where O2 acts as the terminal electron acceptor. However, its entry into the anaerobic respiration route may yield different end products depending on the cell types.

During anaerobic cellular respiration, pyruvate may enter one of the several fermentation pathways depending on the cell type. For example, it enters lactate fermentation pathway in skeletal muscles of animals and Lactic acid bacteria (LAB) (example- Enterococcus, Lactobacillus, Streptococcus, etc.). In hepatocytes (animal) and Saccharomyces cerevisiae (Brewer’s yeast), it enters ethanol fermentation pathway. The fates of pyruvate under aerobic condition (in the mitochondria) and anaerobic condition (ethanol and lactate fermentation pathways) are schematically summarized below.

Fates of Pyruvate under Aerobic and Anaerobic Conditions

Significance of Fermentation during Anaerobic Respiration

The fermentation pathways may serve as the sole source of energy in many obligate anaerobic heterotrophs. These fermentation pathways are also of great significance for the survival of their host cells under hypoxic and anaerobic conditions in facultative and aerobic organisms. For example, Saccharomyces cerevisiae, a facultative anaerobic yeast, carries out ethanol fermentation under hypoxic and anaerobic conditions. The skeletal muscle cells of animals (aerobic organisms) carry out lactate fermentation pathway under hypoxic conditions during short bursts of strenuous activities.

Significance of Fermentation during Anaerobic Respiration

As shown in the picture above, the entry of pyruvate to either of the ethanol and lactate fermentation pathways yield no ATP gain during anaerobic respiration. However, these pathways produce or regenerate NAD+ by converting pyruvate into ethanol or lactate or other respective end product during the process. As shown in picture below, the regenerated NAD+ is again fed into the glycolytic pathway so that there is a continuous supply of 2 ATP even under anaerobic conditions. In aerobic organisms like human, this survival strategy keeps the host cells (say, the skeletal myocytes) alive by providing continuous supply of ATP without requiring oxygen supply for some time.

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