Linear and Branched metabolic pathways

Linear and Branched metabolic pathways

Metabolic pathways are sequences of biochemical reactions that convert one molecule into another. They can be broadly categorized as linear or branched, based on the organization of the pathway and how intermediates are processed.

 

Linear metabolic pathways

A linear fermentation pathway is a series of consecutive, unidirectional biochemical reactions where a single initial substrate is processed through a sequential chain of intermediates, ultimately leading to one or a very limited set of final products. There are no significant alternative routes for intermediates. The primary goal is often the regeneration of NAD+ to keep glycolysis or a similar pathway running, allowing the continuous production of ATP via substrate-level phosphorylation.  These pathways will have simple regulation and a more efficient energy yield per substrate molecule.

Homolactic acid fermentation is an example of a linear pathway.

• Glucose is converted to pyruvate via glycolysis -EMP pathway
• Pyruvate is reduced to lactic acid by lactate dehydrogenase, regenerating NAD+.
• Lactic acid is the only product with a net ATP yield of 2.

Glucose → (glycolysis) → 2 pyruvate

2 pyruvate + 2 NADH → 2 lactic acid + 2 NAD

Another example for a linear pathway is beta-oxidation of fatty acids

Beta-oxidation is the catabolic process by which fatty acid molecules are broken down to generate acetyl-CoA. There is a defined sequence of four enzymatic reactions that repeat until the entire fatty acid chain is broken down, two carbon atoms at a time, into acetyl-CoA units.  ATA generation from beta-oxidation is through the oxidation of its products such as acetyl-CoA, NADH, FADH2, etc in the electron transport chain.

Metabolic regulation in linear pathways is for controlling the rate of the entire pathway so that the cell’s energy demands are met and there is no wasteful overproduction.  The regulation may be done through

Feedback inhibition and allosteric regulation - the end product of the pathway inhibits the activity of an early enzyme in the pathway. For example, excess ATP can inhibit phosphofructokinase-1 in glycolysis. Also, enzymes at key irreversible steps can be allosterically regulated by the binding of activators or inhibitors at sites other than the active site, which will result in the rate of enzyme activity.

Transcriptional control: the synthesis of enzymes involved in the pathway can be upregulated or downregulated at the gene expression level.  This will depend on the substrate availability or environmental conditions.  For example, the rate of the pathway is directly dependent on the availability of the initial substrate such as glucose.

Redox balance: the regeneration of NAD+is of paramount importance. Any disruption in this regeneration will result in a halt of the pathway.

 

Branched metabolic pathways

A branched metabolic pathway is a metabolic network where one or more intermediate compounds can be channelled into multiple, distinct pathways.  This will lead to the production of a diverse array of end products. These branch points help the cell to adapt its metabolism to different environmental conditions, substrates, or specific physiological needs.  These pathways need to be controlled by sophisticated regulatory mechanisms to control each branch point, ensuring the appropriate balance of products.  Branched pathways often give less ATP yield per glucose.  Pentose phosphate pathway, phosphoketolase pathway, etc are examples.

Heterolactic acid fermentation is an example of branched pathway.

• Glucose is processed via the phosphoketolase pathway.
• Cleavage of xylulose-5-phosphate by phosphoketolase into glyceraldehyde-3-phosphate (G3P) and acetyl phosphate is the branch point.
• G3P continues down similar to glycolytic like pathway to form lactic acid.
• Acetyl phosphate may be converted to either ethanol or acetic acid, depending on the enzymes present and the needs of the cell.
• So there are multiple products, lactic acid, ethanol (or acetic acid), and carbon dioxide.

Glucose → (phosphoketolase pathway) → xylulose-5-P → CO2​ + G3P + acetyl phosphate

G3P → (partial glycolysis) → lactic acid

Acetyl phosphate → ethanol (via acetaldehyde) or acetic acid

Other examples of branched fermentation pathways are

• Mixed-acid fermentation: this is carried out by enterobacteriaceae (e.g., E. coli, Salmonella). Pyruvate is a major branch point, leading to diverse products like lactate, acetate, formate, succinate, ethanol, co2​, and h2​.
• Butyric acid fermentation: this is carried out by clostridium species (e.g., Clostridium butyricum). This pathway branches from acetyl-coA, producing butyric acid, butanol, acetone, isopropanol, acetate, co2​, and h2​.
• Propionic acid fermentation: this is carried out by Propionibacterium species. It involves the production of propionic acid, acetic acid, and co₂​.

Metabolic regulation in branched pathways is more complicated.  Here, there is a continuous need of the cell to decide which specific branch to be favoured in response to a changing internal and external environment.

• Allosteric enzymes at branch points: enzymes at the beginning of each branch are often key regulatory points. The accumulation of one end product might inhibit the enzyme responsible for its formation, thus diverting the pathway towards another branch.
• Transcriptional regulation: genes encoding enzymes for specific branches can be induced or repressed based on nutrient availability, ph, redox state, or the presence of specific terminal electron acceptors.
• Redox balance, NADH/NADPH levels or ATP levels: the redox state (ratio of NADH/NAD+or NADPH/NADP+) or the energy status (ATP:ADP:AMP ratio) of a cell influences the choice between different energy-yielding pathways.
• pH homeostasis: The accumulation of acidic end products results in a lower intracellular pH. Some bacteria will shift to produce less acidic products, for example producing ethanol instead of acetic acid, to maintain pH homeostasis.
• Substrate availability: The type and concentration of available sugars can also influence which catabolic pathway to be followed, which in turn impacts the choice of the branch points.

Linear fermentation pathways are optimized for the efficient production of single or very few end products, with relatively straightforward regulation. Branched pathways offer metabolic versatility that allow organisms to generate a wider range of products and adapt to diverse environmental situations, but have lower ATP yield and require more complex regulatory networks.