Direct versus compensatory consequences
Direct consequences
- Follow immediately from the missing catalytic step
- Upstream intermediate accumulates; downstream products deplete
- Flux through the blocked step falls
- Present in every tissue that expresses the pathway
Compensatory consequences
- Appear after the block, as a response to it
- Alternative fuels taken up; intermediates exported; product made elsewhere
- Depend on which tissues can respond
- Absent in tissues that lack the responding capacity
Three errors that break the prediction
- Treating a regulated step as a mere catalytic step. If the missing enzyme was also the point of feedback control, the pathway does not simply lose a reaction — it loses its brake, so the upstream intermediate can keep rising even after the product has fallen.
- Treating an accumulated intermediate as inert. An intermediate that builds up can be chemically reactive, osmotically active, or disruptive to pH, so accumulation is itself a source of harm rather than a harmless backlog.
- Attributing a whole-body symptom directly to the missing enzyme. The symptom is the end of a chain — blocked step, tissue-specific dependence, inter-organ exchange — and naming the enzyme as its cause skips every step that could be tested.
A quick self-check
Before accepting a prediction, ask which parts of it would still hold if the tissue did not depend on the pathway at all. The accumulation-depletion pattern would remain; the energy deficit and the whole-body symptom would not. Anything that disappears under that change is a consequence of tissue context, not of the missing enzyme itself.