Transferring plant biosynthetic genes into a microbial chassis can reproduce enzyme inventories without reproducing the cellular conditions that made the pathway functional in its native organism. This distinction becomes increasingly consequential as heterologous routes incorporate membrane-associated enzymes, redox-intensive reactions, spatially separated intermediates, toxic metabolites, competing precursor demands, and products that require active removal. This article develops an original pathway-compatibility model for interpreting these problems before they are treated as isolated optimization failures. Evidence from microbial production of plant natural products is integrated across five recurrent domains: catalytic and cofactor context, compartmentation and metabolite trafficking, precursor and flux accommodation, toxicity and metabolic burden, and product export. The analysis argues that compatibility is not an intrinsic property of either a pathway or a chassis. It is a conditional relationship between the demands imposed by a particular biosynthetic architecture and the capacities of a particular host under defined operating conditions. The proposed model therefore separates observed production failure from its possible causes, treats compatibility dimensions as potentially interacting rather than automatically additive, and links diagnosis to chassis selection and engineering response. The model is intended as a qualitative decision framework, not a validated score or universal host ranking. Its main limitations are pathway-specific enzyme behavior, incomplete measurement of intracellular states, context-dependent transport and toxicity, and the possibility that process conditions alter the dominant constraint. Prospective cross-host reconstruction and factorial perturbation will be required before predictive claims are justified.
