Metabolic pathways

There are three groups of molecules that form the core building blocks and fuel substrates in the body: carbohydrates (glucose and other sugars); proteins and their constituent amino acids; and lipids and their constituent fatty acids. The biochemical processes that allow these molecules to be synthesized and stored (anabolism) or broken down to generate energy (catabolism) are referred to as metabolic pathways. Glucose metabolism involves the anabolic pathways of gluconeogenesis and glycogenesis, and the catabolic pathways of glycogenolysis and glycolysis. Lipid metabolism involves the anabolic pathways of fatty acid synthesis and lipogenesis and the catabolic pathways of lipolysis and fatty acid oxidation. Protein metabolism involves the anabolic pathways of amino acid synthesis and protein synthesis and the catabolic pathways of proteolysis and amino acid oxidation. Under conditions when glucose levels inside the cell are low (such as fasting, sustained exercise, starvation or diabetes), lipid and protein catabolism includes the synthesis (ketogenesis) and utilization (ketolysis) of ketone bodies. The end products of glycolysis, fatty acid oxidation, amino acid oxidation and ketone body degradation can be oxidised to carbon dioxide and water via the sequential actions of the tricarboxylic acid cycle and oxidative phosphorylation, generating many molecules of the high energy substrate adenosine triphosphate (ATP).

Interplay between metabolic pathways

The interplay between glucose metabolism, lipid metabolism, ketone body metabolism and protein and amino acid metabolism is summarized in Figure 1. Amino acids can be a source of glucose synthesis as well as energy production and excess glucose that is not required for energy production can be stored as glycogen or metabolized to acetyl CoA and stored as fat. Figure 1. Interplay between glucose metabolism, lipid metabolism, ketone body metabolism and amino acid metabolism. See text for details. (Click for enlarged view).
Figure 1. Interplay between glucose metabolism, lipid metabolism, ketone body metabolism and amino acid metabolism. See text for details. (Click for enlarged view).
The catabolism of glucose, lipids and ketone bodies all result in the production of acetyl CoA and the reduced cofactor NADH. Fatty acid β-oxidation also produces the reduced cofactor FADH2. Each acetyl CoA can be oxidized further via the tricarboxylic acid, to generate 2 molecules of CO2, a further 3 molecules of NADH and one molecule of FADH2. Oxidative phosphorylation couples the reoxidation of NADH and FADH2 to the synthesis of ATP. The ATP yields from NADH and FADH2 oxidation are presented in the last section of this article.

Overview of metabolic pathway

Glucose metabolism Despite periods of feeding and fasting, in healthy adults blood sugar levels are maintained between 4 and 7 mM. The balance between the release of glucose into the circulation by either absorption from the intestine or the breakdown of stored glycogen in the liver and the uptake and metabolism of blood glucose by peripheral tissues[1] is controlled by a set of metabolic hormones, insulin, glucagon, the incretins, amylin, leptin, adiponectin, acylation stimulating protein and resistin[2]. A general overview of the actions of these hormones is given in the section ‘Glucose metabolism’.

Anabolic glucose metabolism pathways Gluconeogenesis is the pathway that generates glucose from non-carbohydrate carbon substrates such as pyruvate, lactate, all tricarboxylic acid cycle intermediates (through conversion to oxaloacetate), amino acids other than lysine or leucine, and glycerol[3]. Transamination or deamination of amino acids allows their carbon skeleton to enter the cycle directly (as pyruvate or oxaloacetate), or indirectly via the tricarboxylic acid cycle. The gluconeogenesis pathway consists of eleven enzyme-catalyzed reactions, seven of which are reversible reactions and occur in the degradative pathway glycolysis. Gluconeogenesis is one of the two main mechanisms which keep blood glucose levels from dropping too low. It takes place mainly in the liver and, to a lesser extent, in the cortex of kidneys[3]. Gluconeogenesis occurs during fasting, low-carbohydrate intake or intense exercise, often in association with ketosis[3].

Glycogenesis is a repetitive four step process for the synthesis of glycogen from glucose[4]. It occurs in liver and muscle cells when glucose and ATP are present in relatively high amounts. In the synthesis of glycogen, one ATP is required for every glucose unit incorporated into the polymeric branched structure of glycogen. The glucose (in the form of glucose-6-phosphate) is synthesized directly from glucose or as the end product of gluconeogenesis[4].

Catabolic glucose metabolism pathways Glycogenolysis is the biochemical breakdown of glycogen to glucose. Glycogen is a multi-branched polysaccharide that may contain up to 30,000 glucose units organized with 1→4 (linear) and 1→6 (branched) glycosidic linkages. Two enzymes are involved in removing glucose units (as glucose-1-phosphate) from linear branches and converting it to glucose-6-phosphte for glycolysis[5][6]. Two additional enzymes deal with the transfer of residual four glucose units to the end of a longer glycogen branch, exposing the final glucose at the α[1→6] branching point which is removed by a fourth enzyme as a molecule of glucose, rather than glucose-1-phosphate. In muscle, but not liver cells, the glucose is subsequently phosphorylated to glucose-6-phosphate by a fifth enzyme hexokinase and enters the glycolytic pathway. Glycogenolysis takes place in the cells of muscle and liver tissues in response to hormonal and neural signals. In particular, glycogenolysis plays an important role in the adrenaline-induced fight-or-flight response and the regulation of glucose levels in the blood[7].

Glycolysis is a ten step enzymatic pathway that converts glucose, a six carbon sugar, into two molecules of pyruvate, a 3-carbon ketoacid. Glycolysis occurs in the cytoplasm and does not require the presence of oxygen. It is found (with variations in the terminal steps), in nearly all organisms and is one of the most ancient known metabolic pathways[8]. For each molecule of glucose degraded, glycolysis generates a net 2 molecules of ATP and 2 molecules of NADH + H+. In aerobic organisms the two molecules of pyruvate can be decarboxylated by the three enzyme complex pyruvate dehydrogenase to form acetyl CoA and NADH, H+[9]. The acetyl CoA can be converted into fatty acids and stored as triglycerides or decarboxylated and oxidized via the tricarboxylic acid cycle and oxidative phosphorylation. Reoxidation of the 2 molecules of NADH produced in glycolysis generates a further 5 molecules of ATP but it costs 2 ATP to transport the two NADH from the cytoplasm into the mitochondria, leaving a net gain of 3 ATP[10]. The total gain in ATP via glycolysis is 5 ATP, much less than the additional 25 ATP equivalents generated by the combination of pyruvate dehydrogenase, the TCA cycle and oxidative phosphorylation (see later).

Lipid metabolism

Anabolic lipid metabolism pathways Fatty acid synthesis is a repetitive four step process by which acetyl CoA (derived by decarboxylation of pyruvate, the end product of glycolysis) is converted to fatty acids[11]. The addition of successive two carbons units occurs via malonyl-CoA (generated by the ATP-dependant carboxylation of acetyl-CoA), the elongation reaction being driven by the release of CO2. Fatty acid synthesis occurs in the cytoplasm in contrast to fatty acid oxidation which occurs in the mitochondria[11].

Lipogenesis is the process by which glycerol is esterified with free fatty acids to form triglyceride. Dietary fat (triglycerides), when ingested with food, is absorbed by the gut and transported in the form of plasma-lipoproteins called chylomicrons[11][12]. Lipids are released from their carrier lipoproteins through the local activity of lipoprotein lipase (LPL) and subsequently split into their constituent fatty acids and glycerol. These are taken up by adipose tissue where the triglycerides are resynthesized and stored in cytoplasmic lipid droplets. Lipogenesis also includes the anabolic process by which triglycerides are formed in the liver from fatty acids synthesised from acetyl CoA derived from glucose metabolism described above. Fatty acids generated in the liver, are subsequently esterified with glycerol to form triglycerides that are packaged, not in chylomicrons, but in very low density lipoproteins (VLDLs) and secreted into the circulation[13]. Once in the circulation, VLDLs come in contact with lipoprotein lipase (LPL) in the capillary beds in the body (adipose, cardiac, and skeletal muscle) where LPL releases the triglycerides for intracellular storage or energy production[11].

Catabolic lipid metabolism pathways Lipolysis is the enzymic process by which triacylglycerol, stored in cellular lipid droplets, is hydrolytically cleaved to generate glycerol and free fatty acids[14]. Three enzymes are involved in lipolysis[13]. The free fatty acids can be subsequently used as energy substrates, essential precursors for lipid and membrane synthesis, or mediators in cell signaling processes. The complete oxidation of free fatty acids to generate ATP occurs in the mitochondria by the processes of fatty acid oxidation (β-oxidation). The glycerol component, after conversion in a two-step process to the intermediate glyceraldehyde 3-phosphate, can enter the glycolytic pathway directly and provide energy for cellular metabolism. Alternatively it can be converted to glucose by the process of gluconeogenesis.

Fatty acid oxidation (β-oxidation) is a repetitive four step process by which fatty acids are broken down to produce energy[15]. It involves first getting the fatty acid into the cytosol and then transferring it to the mitochondria where β-oxidation takes place. β-oxidation involves a repeated sequence of four enzyme activities that results in the release of an acetyl-CoA unit, and the generation of a molecule of FADH2 and a molecule of NADH + H+[15]. The acetyl-CoA then enters the tricarboxylic acid cycle (TCA cycle) where it is oxidized to CO2 with the generation of 1 molecule of FADH2 and 3 molecules of NADH + H+. The NADH and FADH2 produced by both fatty acid β-oxidation and the TCA cycle are reoxidized via the electron transport chain to generate ATP by the process of oxidative phosphorylation.

Protein metabolism

Anabolic protein metabolism pathways Amino acid synthesis. Amino acids are categorized into two types - non-essential amino acids (can be synthesized by the body) and essential amino acids which cannot, and have to be provided from the diet[16][17]. The non-essential amino acids are glycine, alanine, serine, asparagine, aspartic acid, glutamine, glutamic acid, proline, cysteine, tyrosine and arginine. The essential amino acids include valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, threonine, lysine and histidine. Arginine, methionine and phenylalanine are considered essential because their rate of synthesis is insufficient to meet the growth needs of the body. Two glycolytic intermediates pyruvate and glyceraldehyde-3-phosphate are precursors to the synthesis of alanine (pyruvate) and serine, glycine and cysteine (glyceraldehyde-3-phosphate)[18]. Two TCA cycle intermediates oxaloacetate and α-ketoglutarate are precursors for the synthesis of aspartic acid and glutamic acid respectively. Aspartic acid is a precursor of asparagine and glutamic acid a precursor of glutamine, proline and ornithine. Tyrosine is produced in cells by hydroxylating the essential amino acid phenylalanine[17].

Protein synthesis. Protein turnover is the balance between protein synthesis and protein degradation[18]. Proteins are naturally occurring polymers made up of repeating units of 20 different amino acids and range from small peptide hormones of 8 to 10 residues to very large multi-chain complexes of several thousand amino acids. Protein synthesis occurs on ribosomes - large intracellular structures consisting of 79 proteins and 6800 nucleotides of ribosomal RNA – and requires a source of amino acids which are either synthesized or come from the proteolytic breakdown of proteins in the gastrointestinal tract or within the cell[18].

Catabolic protein metabolism pathways Proteolysis is the process by which the peptide bonds in proteins are hydrolysed by a combination of proteases and peptidases to generate free amino acids. The proteolytic breakdown of proteins occurs extracellularly in the gastrointestinal tract[19], and intracellularly in lysosomes and proteosomes[20][21][22]. Lysosomal degradation is for proteins of extracellular origin that have been taken up into the cell by endocytosis[21,22]. Proteosomal degradation occurs in large, barrel-shaped, ATP-dependent protein complexes called proteosomes, that digest damaged or unneeded intracellular proteins that have been marked for destruction by the covalent attachment of chains of a small protein, ubiquitin[21,22].

Amino acid catabolism accounts for 10 to 15% of the human body’s energy production[22]. Unlike the situation with glucose and fatty acids, amino acids in excess of those needed for biosynthesis are not stored or excreted but are used as metabolic fuel. Their amino groups are converted into urea through the urea cycle and their carbon skeletons transformed into acetyl CoA, acetoacetyl CoA, pyruvate, or one of the intermediates of the tricarboxylic acid cycle. Depending on their metabolic fates, amino acids are referred to as ‘glucogenic’, ‘ketogenic’ or ‘glucogenic and ketogenic’[22]. Glucogenic amino acids can be converted to pyruvate, α-ketoglutarate, succinyl CoA, fumarate or oxaloacetate and either oxidized into CO2 and H2O to generate ATP via the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation[22] or used to synthesise glucose by the process of gluconeogenesis. In contrast ketogenic amino acids are broken down into acetyl-CoA or the ketone body acetoacetate and used as metabolic fuel as neither of which can bring about net glucose production in humans[23].

Ketone body metabolism Ketogenesis. When the body goes from the fed to the fasted state the liver switches from an organ of carbohydrate utilization and fatty acid synthesis to one of fatty acid oxidation and ketone body production (ketogensis)[24][25]. This metabolic switch is amplified in uncontrolled diabetes. In these states the fat-derived energy (ketone bodies) generated in the liver enters the blood stream and is used by other organs, such as the brain, heart, kidney cortex and skeletal muscle. The two main ketone bodies are acetoacetate and 3-hydroxybutyrate, with acetone the third, and least abundant[23,24]. The presence of elevated ketone bodies in the blood is termed ketosis and the presence of ketone bodies in the urine is called ketonuria. The body can also rid itself of acetone through the lungs which gives the breath a fruity odour. Diabetes is the most common pathological cause of elevated blood ketones. In diabetic ketoacidosis, high levels of ketones are produced in response to low insulin levels and high levels of counter-regulatory hormones[25][26].

Ketolysis is the process by which ketone bodies produced in the liver are converted in non-liver tissues into acetyl CoA which, on complete oxidation via the tricarboxylic acid cycle and oxidative phosphorylation, provides energy for various intracellular metabolic activities[26][27]. Ketolysis occurs in the mitochondria of many extrahepatic organs. The central nervous system is particularly dependent on the delivery of ketone bodies produced in the liver for the process of ketolysis, since ketogenesis occurs very slowly if at all in the central nervous system[26],[27].

Tricarboxylic acid cycle (TCA cycle) The TCA cycle, also known as the citric acid cycle or Krebs cycle, is a key metabolic pathway that unifies carbohydrate, fat, protein and ketone body metabolism[28][29]. The cycle is a series of biochemical reactions employed to generate energy through the oxidation of acetate in the form of acetyl-CoA. The acetyl-CoA can be derived from the degradation of sugars (glycolysis), fats (lipolysis and fatty acid β-oxidation), ketone bodies and amino acids. The cycle comprises eight sequential enzymic reactions that reduce each 2 carbon acetate moiety to two molecules of CO2[27,28]. The energy released by each turn of the cycle is stored either as high energy phosphate in one molecule of GTP, or as high energy electrons in three molecules of NADH + H+ and one molecule of the reduced cofactor, coenzyme Q (QH2) via FADH2[28,29]. The three NADH and one FADH2 produced by each turn of the cycle are re-oxidised and generate ATP in a process called oxidative phosphorylation.

Oxidative phosphorylation Oxidative phosphorylation is the process in which ATP is formed as a result of the transfer of electrons from the reduced cofactors, NADH or FADH2, to O2 by a series of electron carriers[30][31]. There are two stages in the process. The first involves the electron transport chain, a series of four protein complexes that re-oxidize the NADH and FADH2 cofactors generating a proton motive force that pumps protons (hydrogen ions) out of the mitochondrial matrix into the intermembrane space, creating an electrical potential across the inner mitochondrial membrane[30,31]. The second stage involves ATP synthase, a large, multi-enzyme complex which mechanically couples the chemical synthesis of ATP to the electrochemical flow of these protons down the concentration gradient back across the inner mitochondrial membrane into the mitochondrial matrix[30,31]. The ATP synthase complex is composed of two rotator motors mounted on a central shaft and held together by an eccentric bearing. The theoretical yield from oxidative phophorylation is 3 ATP per NADH and 2 ATP per FADH2. Inefficiencies reduce the actual yield to ~2.5 per NADH and 1.5 per FADH2[30,31].

Intracellular location of metabolic pathways

Figure 2. Connections between cytoplasmic and mitochondrial metabolic intermediates. (Click for enlarged view).
Figure 2. Connections between cytoplasmic and mitochondrial metabolic intermediates. (Click for enlarged view).
There are two main intracellular compartments involved in metabolism: the cytoplasm and mitochondria. The pathways involved in sugar metabolism - glycolysis, gluconeogenesis, glycogenolysis and glycogenesis – all occur in the cytoplasm as do three of the lipid metabolism pathways - lipolysis, lipogenesis and fatty acid synthesis, and the pathways for protein synthesis and intracellular proteolysis. In contrast the pathways for fatty acid oxidation, ketone body synthesis and oxidation, the tricarboxylic acid cycle and oxidative phosphorylation all occur in mitochondria. The way in which some metabolic intermediates are shuffled between these intracellular compartments is shown in Figure 2.

Comparative energy yields from carbohydrate and lipid catabolism

Glucose metabolism Figure 3 - Glucose oxidation equations. Click to enlarge
Figure 3 - Glucose oxidation equations. Click to enlarge
Figure 4 - Fatty acid oxidation equations. Click to enlarge
Figure 4 - Fatty acid oxidation equations. Click to enlarge
The equations summarizing the complete oxidation of glucose are displayed in in Figure 3[32].

Lipid metabolism - fatty acid oxidation The equations summarizing the complete oxidation of the C18 fatty acid (stearate) are displayed in Figure 4.


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