Due to the potential lethality of NO, cells benefitted greatly from the evolution of an enzyme capable of catalyzing the conversion of toxic NO to nitrate.

In addition to numerous flavohemoglobins, many distantly related members of the hemoglobin superfamily including the muscle myoglobin, the non-symbiotic plant hemoglobin and symbiotic plant leghemoglobin, the neuronal neuroglobin, and the mammalian cytoplasmic cytoglobin[15][16] appear to function as nitric oxide dioxygenases (NODs), although the cellular electron donor(s) for many globins have yet to be defined.

Historically, nitric oxide dioxygenase (around 1.8 billion years ago) served to provide the modern day analogue of hemoglobin/myoglobin function for oxygen storage and transport.

[6] The wide diversity of multicellular organisms benefitting from the oxygen storage and transport functions of myoglobin/hemoglobin appeared much later (approximately 0.5 billion years ago).

NODs are now known to serve two important physiological functions in diverse life forms: they prevent NO toxicity (otherwise known as "nitrosative stress") and regulate NO signalling.

[2] NODs belong to the larger family of well-established free radical and reactive oxygen detoxifying enzymes that includes superoxide dismutase, catalase, and peroxidase.

This approach demonstrated that flavoHb is indeed enzymatically active within human and murine cells and potently blocks exogenous and endogenous sources of nitrosative stress.

[26] This technology was then extended to interrogate the role of NO synthesis in the highly tumorigenic cancer stem cells (CSCs) from human glioblastoma (brain tumor) samples.