Reconstructing plant natural-product pathways outside their native organisms is often framed as a choice among established production hosts, yet pathway success depends on biochemical requirements that differ substantially among molecules. Yeast, bacterial, and plant-cell systems offer distinct combinations of membrane organization, redox physiology, precursor metabolism, transport capacity, compartmentation, tolerance, and engineering accessibility. Consequently, a chassis that performs well for one pathway may impose avoidable engineering burdens on another. This article develops a proposed molecule-centered comparative decision model for selecting among yeast, bacterial, plant-cell, and, where appropriate, hybrid production architectures. The analysis distinguishes intrinsic or readily available host compatibility from engineering flexibility and argues that chassis selection should begin with the pathway's molecular dependencies rather than host familiarity or platform popularity. Decision-relevant features include membrane-bound tailoring chemistry, cofactor and redox-partner requirements, nucleotide-sugar demand, intracellular localization, transport, product toxicity, pathway topology, side-reaction risk, and the extent to which pathway modules can be separated. Recent reconstructions show that chemically demanding pathways can be realized in more than one chassis, but the engineering burden is redistributed rather than eliminated. The proposed model therefore treats chassis choice as conditional and multidimensional, permits deliberate use of incomplete cellular reconstructions and hybrid architectures, and separates biosynthetic feasibility from manufacturing readiness. Its principal limitation is that existing evidence is dominated by pathway-specific demonstrations rather than standardized prospective cross-host comparisons. The framework should therefore be considered a testable decision architecture, not a validated universal ranking of host systems.
