Porphobilinogen synthase (PBGS) is an essential enzyme that catalyzes an early step in heme biosynthesis. An unexpected human PBGS quaternary structure dynamic drove the definition of morpheeins, which are protein multimers that dissociate, change shape, and re-assemble differently with functional consequences. Each PBGS monomer has two domains that can reposition through a hinge motion. Human PBGS exists in an equilibrium among high activity octamer, low activity hexamer, and low mole-fraction dimer in which the hinge motion occurs. The dimer conformation dictates the multimer architecture. An octamer-specific inter-subunit interaction responds to pH, resulting in a pH-dependence to the octamer-hexamer equilibrium. An inborn error of metabolism, ALAD porphyria, is caused by single amino acid substitutions that stabilize the hexamer relative to octamer. Drugs that stabilize the PBGS hexamer result in a drug side effect that can exacerbate porphyria. PBGS is essential for all organisms that require respiration, photosynthesis, or methanogenesis. Consequently, phylogenetic variation in PBGS multimerization equilibria provides insight into how Nature has harnessed oligomeric variation in the control of protein function. The dynamic multimerization of PBGS revealed the morpheein mechanism for allostery, a structural basis for inborn errors of metabolism, a quaternary structure focus for drug discovery and/or drug side effects, and a pathway toward new antibiotics or herbicides. The fortuitous discovery of PBGS quaternary structure dynamics arose from characterization of a low-activity single amino acid variant that dramatically stabilized the hexamer, whose existence had previously gone unnoticed.

胆色素原合酶（PBGS）是一种必需的酶，可催化血红素生物合成的早期步骤。意外的人类PBGS季结构动态推动了吗啡素的定义，吗啡素是蛋白质多聚体，其解离，改变形状并以不同的方式重新组装，从而产生功能性后果。每个PBGS单体都有两个可以通过铰链运动重新定位的区域。人PBGS在发生铰链运动的高活性八聚体，低活性六聚体和低摩尔分数二聚体之间处于平衡状态。二聚体构象决定了多聚体体系结构。八聚体特异的亚基间相互作用会响应pH值，导致pH依赖于八聚体-六聚体平衡。代谢的先天性错误，ALAD卟啉症，这是由于相对于八聚体稳定六聚体的单个氨基酸取代引起的。稳定PBGS六聚体的药物会导致药物副作用，从而加剧卟啉症。PBGS对于所有需要呼吸，光合作用或甲烷生成的生物都是必不可少的。因此，PBGS多聚体平衡中的系统发育变异为洞察自然界如何利用寡聚变异控制蛋白质功能。PBGS的动态多聚化揭示了吗啡肽的变构机制，先天性代谢错误的结构基础，药物发现和/或药物副作用的四级结构焦点以及通向新抗生素或除草剂的途径。