Interactive binding to the two principal ligand binding sites of human serum albumin: effect of the neutral-to-base transition

Evidence for pH-dependent multiple conformers in iron(II) heme–human serum albumin: spectroscopic and kinetic investigation of carbon monoxide binding

“…Furthermore, this behavior, which underlies the occurrence of multiple conformations of iron(II) heme-HSA, may have great impact on the function of heme-HSA as a metabolite and drug transporter, since this proton-linked modulation is reflected in its capability of interacting with molecules circulating in the bloodstream, as previously demonstrated [3,8,20,22,[29][30][31][32]. Therefore, HSA, not only acting as a heme carrier but also displaying transient heme-based properties, represents a case for ''chronosteric effects'' [62], which opens the scenario toward the possibility of a time-and metabolite-dependent multiplicity of roles for HSA.…”

“…According to Sudlow's nomenclature, bulky heterocyclic anions bind preferentially to Sudlow's site I (located in subdomain IIA), whereas Sudlow's site II (located in subdomain IIIA) is preferred by aromatic carboxylates with an extended conformation ( Fig. 1) [3,11,[18][19][20][21][22][23][24]. Among others, HSA is able to bind 7 equiv of long-chain fatty acids (FAs) at multiple binding sites (labeled FA1 to FA7) ( Fig.…”

“…At pH [ 8.0 and in the absence of ligands, HSA exhibits the basic form, which is characterized by a high affinity for some ligands (e.g., heme). Ligands that bind with the highest affinity to one of the conformational states may allosterically modulate the HSA transition [3,8,20,22,[29][30][31][32].…”

The extraordinary ligand binding properties of human serum albumin

“…Between pH 4.3 and 8.0 and in the absence of allosteric effectors, HSA displays the neutral (N) form which is characterized by the heart-shaped structure. Between pH 4.3 and 8.0 in the presence of allosteric effectors (e.g., drugs and long-chain FAs) and at pH greater than 8 in the absence of ligands, HSA changes conformation to the basic (B) form with the loss of a-helix and an increased affinity for some ligands, like warfarin (10,32,34,39,43,44,46,47).…”

“…The inhibitory allosteric effect of ferric heme on ligand binding to Sudlow's site I may be due to stabilization of the Neutral (N) state of HSA, which occurs between pH 4.3 and 8.0 (in the absence of allosteric effectors). Conversely, ligand binding to Sudlow's site I may impair the ferric heme-HSA formation by stabilizing the Basic (B) state of HSA, occurring between pH 4.3 and 8.0 in the presence of allosteric effectors and at pH greater than 8.0 in the absence of ligands (6,10,32,39,40,48).…”