Amphibolic Pathway

A metabolic pathway involves a series of chemical reactions wherein a particular molecule undergoes transformations, resulting in a specific product(s). Each step in a metabolic pathway is catalyzed by enzymes. Metabolic reactions manage the resources of the cell via two kinds of processes, namely the anabolic pathway and the catabolic pathway. The former is a constructive pathway and involves biosynthesis or the building of new molecules. Such reactions require energy input, usually in the form of ATP.

The latter on the other hand, is a degradative pathway, leading to the breakdown of substances. These kinds of pathways would require an input of energy. Interestingly, some metabolic reactions have elements of catabolism and anabolism, i.e., they involve the breakdown of certain molecules and produce certain other molecules which serve as precursors for the synthesis of biomolecules. Such pathways are referred to as amphibolic pathways. This article attempts to highlight the amphibolic nature of the respiratory pathway.

What is an Amphibolic Pathway?

A biochemical pathway that involves the processes of both anabolism and catabolism is termed an amphibolic pathway. In such pathways, catabolic end products or intermediates are used as precursors and supply free energy for the synthesis of other molecules.

Is Glycolysis an Amphibolic Pathway?

Glucose occupies a central position in the metabolism of plants, animals, and many microorganisms. It is used to produce energy in the form of ATP through the process of aerobic or anaerobic respiration. Glycolysis involves the conversion of glucose through a series of reactions, to two molecules of pyruvate.

While it is mainly studied as a catabolic process, involving the breakdown of glucose, there are some intermediates of the pathway that are utilized in the synthesis of some biomolecules. Hence, we can say that glycolysis is an amphibolic pathway.

• The pentose phosphate pathway utilizes the first intermediate of glycolysis, i.e., Glucose 6-Phosphate, ultimately leading to the formation of Ribose 5-Phosphate, which in turn, is used in the nucleotide synthesis. Erythrose 4-phosphate produced in the pentose phosphate pathway is used in the synthesis of aromatic amino acids.

• The glyceraldehyde 3-phosphate produced is used in the production of glycerol which in turn is required for the synthesis of phospholipids.

• Pyruvate, the glycolytic pathway's end product, is further metabolized to Acetyl-CoA, which is used in fatty acid biosynthesis.

• The NADPH produced in the pentose phosphate pathway (which uses intermediates of glycolysis) is used as a reductant to drive several anabolic reactions including fatty acid biosynthesis, nucleic acid biosynthesis, carotenoid biosynthesis, etc.

Krebs Cycle- An Amphibolic Pathway

The Krebs Cycle (also known as the TCA cycle) is amphibolic in aerobic organisms, as it is involved in both the catabolic process and the anabolic reactions as well. During Krebs Cycle, which occurs in the mitochondria, ATP, NADPH and FADH2 are produced. Acetyl-CoA is the central molecule of the Krebs Cycle and is obtained from.

• Pyruvate oxidation (from glycolysis)

• Fatty Acids (Beta-oxidation)

• Amino acid degradation

Krebs Cycle involves the complete oxidation of Acetyl-CoA into carbon dioxide (CO₂) and therefore, is catabolic.

The Krebs cycle is also said to be anabolic as the intermediates of this cycle are used as precursors for the biosynthesis of several biomolecules, including nucleic acids, fatty acids, amino acids, and porphyrins. Oxaloacetate, an intermediate of the Krebs cycle, is regenerated at each turn of the cycle so that it may condense with another molecule of Acetyl-CoA and keep the cycle going.

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The intermediates of the Krebs Cycle serve the following anabolic functions.

• Succinyl-CoA is used for the synthesis of porphyrins that are involved in the production of haemoglobin and myoglobin.

• Oxaloacetate is the precursor for synthesising amino acids like proline, alanine, glutamate, and aspartate, via transamination reactions. Glutamate and aspartate in turn are used in the synthesis of purines.

• Oxaloacetate is also converted to phosphoenolpyruvate in the mitochondria which is then converted into glucose in the gluconeogenesis pathway. Alternatively, malate is also used for gluconeogenesis.

• 𝛂- Ketoglutarate is used in the production of succinate.

• 𝛂- Ketoglutarate is also involved in the synthesis of glutamate and pyruvate by transamination reactions.

• Citrate reacts with CO₂ to form Acetyl-CoA which is the starting material for the synthesis of fatty acids and cholesterol.

  • The fatty acids are further metabolised into triacylglycerols and diacylglycerols and ultimately form the phospholipids.

  • The cholesterol is then used to synthesise steroids and bile acids.

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Figure− The amphibolic nature of the Krebs Cycle. Only those intermediates are shown which are involved in anabolic pathways.

Hence, Krebs Cycle can safely be termed as an amphibolic cycle, involving both, catabolic and anabolic reactions.

How is the Respiratory Pathway an Amphibolic Pathway?

Respiration is the process by which complex substances are broken down into simpler substances to provide organisms energy, in the form of ATP. Respiration is typically studied under four stages including glycolysis, pyruvate oxidation, tricarboxylic acid cycle and oxidative phosphorylation. Of these, glycolysis and the tricarboxylic acid cycle produce intermediates that are involved in the synthesis of various other biomolecules.

Glycolysis

• Glyceraldehyde 3-phosphate produced in glycolysis is used in the synthesis of phospholipids.

• The end product of glycolysis, namely pyruvate is further metabolised into Acetyl-CoA, which enters the Krebs cycle.

Krebs Cycle

• Four intermediates of the Krebs Cycle are important precursor metabolites in the anabolic reactions of the cell, viz., citrate (biosynthesis of fatty acids and sterols), 𝛂- Ketoglutarate (synthesis of amino acids and nucleotides), succinyl CoA (synthesis of porphyrins), and oxaloacetate (synthesis of amino acids and purines).

Pentose Phosphate Pathway

• Pentose Phosphate Pathway branches out from glycolysis, utilising the first intermediate of glycolysis, glucose 6-phosphate.

• The pentose phosphate pathway results in the formation of ribose 5-phosphate, which is importantly involved in the synthesis of nucleotides, specifically in the biosynthesis of purine bases leading to the synthesis of DNA and RNA, and in the synthesis of histidine.

• The pentose phosphate pathway also produces erythrose 4-phosphate, which is involved in the synthesis of aromatic amino acids like tryptophan, phenylalanine and tyrosine.

Therefore, in conclusion, the respiratory pathway is an amphibolic pathway, as it involves the production of several precursor metabolites which are used in the biosynthesis of many cellular molecules, along with the oxidation of organic carbon into carbon dioxide and water, releasing energy.

Differences between Krebs Cycle and Glycolysis

Glycolysis	Krebs Cycle
Occurs in the cytoplasm	Occurs in the mitochondrial matrix
It is a linear pathway	It is a cyclic pathway
First step of respiration	It is the third step in respiration, after glycolysis and pyruvate oxidation
Begins with glucose	Begins with Acetyl-CoA
Incomplete oxidation of glucose into 2 molecules of pyruvate	Complete oxidation of Acetyl-CoA into CO2
Consumes 2-ATP	No ATP consumption involved
Generates 2-ATP, NADH + 2H+ per glucose molecule	Generates 1 ATP, 3 NADH per turn of the cyle
No release of CO2	CO2 released
An occur in absence of oxygen	Essentially, it is a part of aerobic respiration
Net ATP generated = 8 ATP	Net ATP generated = 24

Conclusion

• Amphibolic pathways are both catabolic and anabolic.

• Catabolic intermediates of some pathways are used as precursor metabolites for synthesis of other biomolecules.

• Glycolysis involves breakdown of glucose to yield pyruvate which undergoes oxidative decarboxylation to yield Acetyl-CoA, which enters the TCA cycle.

• Intermediates of glycolysis, namely glucose 6-phosphate and glyceraldehyde 6-phosphate are used in other pathways, yielding purines and phospholipids respectively.

• Krebs Cycle is a well-known amphibolic pathway, its intermediates are used in fatty synthesis of fatty acids and sterols, purines , pyrimidines and various amino acids.

• The respiratory pathway as a whole includes various catabolic intermediates that serve as anabolic precursors, and hence, respiratory pathway is said to be amphibolic.

FAQs

Q1. What are anaplerotic pathways?

Ans. Anaplerotic pathways serve to replenish the Krebs Cycle intermediates that are used for synthesis reactions. Examples of anaplerotic reactions include the pyruvate carboxylase reaction and the PEP carboxylase reaction which replenish oxaloacetate.

Q2. Why isn't Acetyl-CoA derived from pyruvate directly used for fatty acid synthesis?

Ans. Krebs Cycle occurs in the mitochondria while fatty acid synthesis is a cytosolic reaction. Since Acetyl-CoA cant be moved to the cytosol, citrate is converted to Acetyl-CoA via citrate lyase, to facilitate the synthesis of fatty acids.

A3. What enzyme is involved in the conversion of 𝛂- Ketoglutarate to glutamate?

Ans. Alanine transaminase.

Q4. Which enzyme of the TCA cycle is found in the mitochondrial membrane?

Ans. Succinate dehydrogenase.

Q5. Which enzyme links glycolysis to the Krebs cycle?

Ans. Pyruvate decarboxylation reaction links glycolysis to Krebs Cycle, catalysed by the pyruvate dehydrogenase complex .