Table of Contents
Metabolic pathways are ordered sequences of chemical reactions in cells, where the product of one reaction becomes the substrate (starting material) for the next. In this chapter, the focus is on how such pathways are organized and why that organization matters, not on the detailed steps of particular pathways such as glycolysis or photosynthesis.
Linear, Cyclic, and Branched Pathways
Metabolic pathways can be grouped by their overall shape or topology.
Linear pathways
In a linear pathway, substrates are converted stepwise to a final product without returning to an earlier intermediate:
$$
A \rightarrow B \rightarrow C \rightarrow D \rightarrow \text{Product}
$$
Features:
- Each intermediate is used mainly to progress to the next step.
- Many degradation (catabolic) and synthesis (anabolic) routes are largely linear (e.g., the main chain of glycolysis).
Linear design allows:
- Clear beginning and end points.
- Easier regulation at a few key steps (often early and near-irreversible reactions).
Cyclic pathways
In cyclic pathways, a starting molecule is regenerated at the end of the cycle. Only certain atoms from incoming substrates are changed or removed, but the core cycle compounds recur:
$$
A \rightarrow B \rightarrow C \rightarrow D \rightarrow A
$$
Examples (covered in detail elsewhere):
- Citric acid cycle (Krebs cycle)
- Calvin cycle in photosynthesis
Key ideas about cycles:
- The “cycle” compounds act somewhat like catalysts: they are not consumed overall but are necessary for the reactions to proceed.
- The cycle can run continuously as long as entry substrates and energy sources (e.g. NADH, ATP, light) are supplied.
- Regulation often occurs at entry and exit points of the cycle and at a few key internal steps.
Branched pathways and metabolic networks
Many pathways are not strictly linear or cyclic but have branches:
- Branch point (node): an intermediate can be used in more than one pathway.
- Example pattern:
$$
A \rightarrow B \rightarrow C \rightarrow D
$$
with a branch:
$$
C \rightarrow E \rightarrow F
$$
Consequences of branching:
- The cell can redirect material (metabolites) according to needs (e.g., from energy production to biosynthesis).
- Competition for the same intermediate means that flux into one branch affects availability for others.
- Many individual pathways connect into a metabolic network, with thousands of reactions and intermediates in complex organisms.
Directionality and Reversibility in Pathways
Within pathways, some reactions are readily reversible, while others effectively proceed only in one direction under cellular conditions.
Reversible reactions
- Have small changes in free energy ($\Delta G$) under cellular conditions.
- Can proceed in either direction depending on concentrations of substrates and products.
- Help maintain near-equilibrium states for many intermediates.
- Allow pathways to be used in both directions (e.g., in both breakdown and synthesis) when combined with other steps.
Irreversible (or effectively irreversible) reactions
- Have large negative $\Delta G$ in the cellular context.
- Proceed in practice in one direction.
- Often use high-energy compounds like ATP.
- Commonly serve as control points in pathways.
In many pathways:
- A few steps are strongly irreversible and act like “valves.”
- Many other steps are near-equilibrium and follow the direction set by those key steps.
This distribution of reversible and irreversible reactions makes pathways:
- Directional when needed (for efficient flow from substrate to product).
- Flexible enough to reverse or reroute flux when circumstances change, as long as alternative irreversible steps are provided.
Pathways as Series of Enzyme-Catalyzed Steps
Each step in a metabolic pathway is catalyzed by a specific enzyme. This has several consequences.
Specificity and order
- Each enzyme converts one (or a few closely related) substrates into a specific product.
- Enzymes are often arranged so that:
$$
\text{Enzyme}_1: A \rightarrow B \\
\text{Enzyme}_2: B \rightarrow C \\
\text{Enzyme}_3: C \rightarrow D
$$
- The right enzymes must be present and active for the pathway to function.
Metabolic intermediates
The compounds formed between the first substrate and the final product are called intermediates or metabolites. Many intermediates are:
- Shared by multiple pathways.
- Used as building blocks (e.g., amino acid precursors) or as entry points for other routes.
Substrate channeling and organization
In some cases, enzymes in a pathway:
- Are physically associated into complexes, or
- Are organized in specific cell regions or on membranes.
This can lead to:
- Substrate channeling: intermediates are passed directly from one enzyme to the next, often increasing speed and limiting side reactions.
- Local “micro-environments” where certain reactions are favored.
Details of enzyme structure and function, and of enzyme regulation, are discussed in a separate chapter, but it is important here that the pathway structure depends entirely on the set of enzymes that the cell actually produces.
Anabolic and Catabolic Pathways
Metabolic pathways can be grouped functionally by what they achieve for the cell.
Catabolic pathways
Catabolic pathways mainly:
- Break down larger molecules into smaller ones.
- Release energy, which is captured in usable forms (such as ATP and reduced coenzymes).
General pattern:
$$
\text{Large, energy-rich molecule} \rightarrow \text{smaller molecules} + \text{usable energy}
$$
Catabolic pathways tend to:
- Be oxidative (electrons are removed from substrates).
- Feed into a limited number of central “hub” pathways (e.g., those leading to ATP production).
Anabolic pathways
Anabolic pathways mainly:
- Build complex molecules from simpler ones.
- Consume energy (often ATP) and reducing power (e.g., NADPH).
General pattern:
$$
\text{Small precursors} + \text{energy} \rightarrow \text{larger, more complex molecule}
$$
These pathways:
- Are essential for growth, repair, and reproduction.
- Often start from central intermediates generated by catabolic routes.
Amphibolic pathways
Some pathways can function both in breakdown and in synthesis, depending on conditions. These are called amphibolic.
- For example, an intermediate step sequence can serve in energy production when used in one direction, but support biosynthesis in another context.
Amphibolic design:
- Reduces the need for separate, completely distinct pathways.
- Requires careful regulation so that opposing processes do not run at full speed simultaneously and waste energy.
Compartmentation of Metabolic Pathways
In eukaryotic cells, different pathways often occur in different cellular compartments (organelles or defined regions). Prokaryotic cells lack membrane-bound organelles but can still show spatial organization.
Reasons for compartmentation
Compartmentation allows cells to:
- Separate incompatible reactions (e.g., those requiring different pH or redox conditions).
- Maintain specific concentrations of metabolites and ions.
- Target regulation to specific locations.
- Channel intermediates efficiently between enzymes in the same compartment.
Types of compartmentation
Examples of common patterns (without going into detailed organelle functions):
- Certain catabolic steps (energy-yielding) concentrated in specific internal membranes.
- Many anabolic pathways (biosynthetic) located in the cytosol or other defined compartments.
- Storage and breakdown pathways separated in space and time (e.g., seasonal or developmental changes leading to relocation or altered activity).
Compartmentation influences how pathways connect: intermediates often must cross membranes using specific transport proteins to link one compartment’s pathway to another’s.
Pathway Regulation and Control Points
Although detailed mechanisms of enzyme regulation are treated elsewhere, the logic of regulation at the pathway level is important here.
Key control steps
A metabolic pathway usually has a few rate-limiting or committed steps:
- The rate-limiting step is often the slowest or most tightly regulated step that largely determines the overall pathway flux (rate of throughput).
- A committed step leads to an intermediate that is used almost exclusively for one pathway, effectively “committing” that substrate to a particular fate.
These steps:
- Are usually catalyzed by enzymes that carry out irreversible reactions (under cellular conditions).
- Are the main targets for regulation by the cell.
Feedback regulation
Common principles:
- Feedback inhibition: the final product of a pathway inhibits an early enzyme in the same pathway. This prevents overproduction.
- Feed-forward activation: an early intermediate activates a later step, helping to coordinate flow through the pathway.
Benefits:
- Automatic self-adjustment without the need for external “control centers.”
- Efficient use of resources.
Cross-regulation at branch points
At branch points, the cell must decide how much flux goes into each branch. Principles include:
- Product of branch 1 inhibits the enzyme that directs flux into branch 1, favoring branch 2 when product 1 is abundant.
- Product of branch 2 may inhibit its own branch in a similar fashion.
- Some enzymes at branch points respond to signals reflecting overall energy state (e.g., ATP/ADP ratios, redox state), linking local decisions to global conditions.
Thus, pathway topology (including branches and cycles) helps determine how and where regulation is most effective.
Convergence and Divergence in Metabolic Pathways
Metabolism is not just a set of isolated lines; it shows characteristic patterns of convergence and divergence.
Convergent catabolism
Many different starting substances can be broken down to a smaller number of common intermediates.
- Diverse fuels (various carbohydrates, fats, amino acids) may all be funneled into a limited set of central pathways.
- This convergence simplifies the design: a few central pathways handle energy extraction from many sources.
Divergent anabolism
From a relatively small pool of common intermediates, cells can synthesize a wide variety of complex molecules.
- A few central metabolites serve as branch points to numerous biosynthetic pathways (e.g., for amino acids, nucleotides, lipids).
- This divergence allows great chemical diversity in cells based on a shared core metabolism.
Convergence and divergence together create a “hub-and-spoke” structure:
- Central hubs: shared intermediate pools and energy-converting pathways.
- Spokes: specialized biosynthetic or degradative routes.
Metabolic Integration and Homeostasis
All metabolic pathways together must support a stable internal environment (homeostasis), even when external conditions vary.
Balancing supply and demand
- Energy balance: ATP-producing pathways and ATP-consuming pathways must be coordinated so that supply matches demand.
- Precursor balance: when building blocks are needed (for growth, repair, or storage), flux is diverted from pure energy production toward biosynthesis.
- Redox balance: pathways that generate and consume reducing equivalents (like NADH, NADPH) must be balanced to maintain appropriate redox states.
Responses to changes
Changes in:
- Nutrient availability
- Activity level (e.g., in animals)
- Environmental variables (temperature, light, etc.)
lead to shifts in:
- Which pathways are active,
- How fast they run,
- Which branches are favored.
This dynamic adjustment is mainly accomplished by:
- Altered enzyme activity (rapid),
- Changes in enzyme amounts (slower, via gene expression),
- Modulation of transport steps between compartments and across membranes.
In summary, metabolic pathways are not rigid pipelines; they are flexible, interconnected routes whose shapes (linear, cyclic, branched), locations (compartments), and control points (regulated steps) together allow the cell to adapt and maintain internal stability while transforming matter and energy.