How might a cigarette-smoke chemical change hemoglobin so that it holds oxygen too tightly?

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Cigarette smoking is known to cause hypoxia—an inadequate supply of oxygen to tissues—in addition to life-threatening diseases such as lung cancer and cardiovascular disease. Hypoxia plays a pivotal role in the development of chronic obstructive pulmonary disease. Smoking during pregnancy also poses risks to the unborn child.

Besides carbon monoxide, the attachment of cigarette-smoke-derived para-benzoquinone (pBQ) to human hemoglobin (HbA) has been reported to contribute to hypoxia. The abstract describes pBQ attachment as more alarming than carbon monoxide because it is an irreversible covalent modification.

In this laboratory study of pBQ-conjugated human hemoglobin (Hb-pBQ), a functional assay using an oxygen equilibrium curve showed significant decreases in both P50 and cooperativity of oxygen binding. The structural changes associated with this altered function had remained unknown.

The researchers used the enhanced sensitivity and high resolution of nano-ESI mass spectrometry to investigate the native structure of hemoglobin oligomers in a single scan. They assessed the structural integrity of Hb-pBQ through dissociation equilibrium constants (Kd). Compared with HbA, the Kd values for the tetramer–dimer and dimer–monomer equilibria increased by 4.98-fold and 64.3-fold, respectively.

Isotope exchange mass spectrometry revealed perturbed interactions between subunits in both the deoxygenated and oxygenated states of Hb-pBQ. However, monitoring the collision cross-sectional area showed no change in its three-dimensional architecture.

The researchers propose that pBQ attachment significantly destabilizes hemoglobin’s functionally active structure, resulting in tighter oxygen binding that leads to hypoxia.