Heme-based catalytic properties of human serum albumin

Abstract

Human serum albumin (HSA): (i) controls the plasma oncotic pressure, (ii) modulates fluid distribution between the body compartments, (iii) represents the depot and carrier of endogenous and exogenous compounds, (iv) increases the apparent solubility and lifetime of hydrophobic compounds, (v) affects pharmacokinetics of many drugs, (vi) inactivates toxic compounds, (vii) induces chemical modifications of some ligands, (viii) displays antioxidant properties, and (ix) shows enzymatic properties. Under physiological and pathological conditions, HSA has a pivotal role in heme scavenging transferring the metal-macrocycle from high- and low-density lipoproteins to hemopexin, thus acquiring globin-like reactivity. Here, the heme-based catalytic properties of HSA are reviewed and the structural bases of drug-dependent allosteric regulation are highlighted.

Figure 1

Three-dimensional structure of HSA complexed with endogenous and exogenous ligands bound to the FA sites. The subdomains of HSA are rendered with different colors (domain IA, in blue; domain IB, in cyan; domain IIA, in forest green; domain IIA, in green; domain IIIA, in yellow; domain IIIB, in orange). The FA1-salicylic acid (PDB ID: 2I30), F2-capric acid (PDB ID: 1E7E), FA3-FA4-ibuprofen (PDB ID: 2BXG), FA5-propofol (PDB ID: 1E7A), FA6-halothane (PDB ID: 1E7C), FA7-warfarin (PDB ID: 2BXD), F8-capric acid (PDB ID: 1E7E), and FA9-thyroxine (PDB ID: 1HK4) complexes are highlighted. Three molecules of halothane are bound in the FA6 site. The picture has been drawn with the UCSF Chimera package.^,

Figure 2

Drug-dependent six coordination of the heme-Fe atom of HSA-heme. Superposition of the crystal structure of HSA-heme-Fe(III) (light green and forest green, PDB entry 1O9X) and of the binary drug-bound HSA-heme-Fe(III) complex (hot pink and red). Heme-Fe(III), His146 and Tyr161 are highlighted. The picture has been drawn using the UCSF Chimera package.^,

Scheme 1

Peroxynitrite scavenging by HSA-heme-Fe(II)-NO.

Scheme 2

Peroxynitrite detoxification by HSA-heme-Fe(III)

Scheme 3

The HSA-heme-Fe(II)-catalyzed conversion of NO₂^– to NO.

Scheme 4

O₂-based scavenging of NO-bound HSA-heme-Fe(II).

Scheme 5

Catalase and peroxidase activity of HSA-heme-Fe(III).