Novel insights into the pleiotropic effects of human serum albumin in health and disease

Background

Human serum albumin is the principal protein in human serum. It participates in regulation of plasma oncotic pressure and transports endogenous and exogenous ligands such as thyroxine, free fatty acids, bilirubin, and various drugs. Therefore, studying its ligand binding mechanism is important in understanding many functions of the protein.

Scope of review

This review discusses the pleiotropic biochemical effects and their relevance to physiologic functions of albumin.

Major conclusions

Although HSA is traditionally recognized for its ligand transport and oncotic effects in human circulation, our studies have revealed its participation in several other important physiological functions. In some instances, it may function as a catalyst. Pleiotropic properties of HSA have been exploited by development of recombinant HSA and its mutants, and the use of these recombinant proteins in studies with various biochemical and biophysical techniques. These studies allowed us to obtain new insights on the diverse roles of HSA in human physiology. The following aspects of HSA were discussed in this review: 1) HSA and its mutants' role in thyroxine transport, 2) structural details of the ligand binding functions of HSA to ligands such as warfarin, digoxin, halothane anesthetics, nitric oxide, bilirubin, free fatty acids, etc, and 3) the formation of modified albumin during myocardial ischemia, its diagnostic significance, and HSA's role in cardiovascular disease.

General significance

The appreciation and understanding of structural details and new physiological roles has provided a renewed interest in HSA research. Specific structural information gained on various mechanisms of HSA–ligand interaction can be used to develop a model to better understand protein–drug interactions, aid in the development of new drugs with improved pharmacokinetic effects, and ultimately be used to improve the quality of healthcare. This article is part of a Special Issue entitled Serum Albumin.     

Lipid peroxidation in neurodegeneration: new insights into Alzheimer's disease

Imbalances of oxidative homeostasis and lipid peroxidation have been revealed as important factors involved in neurodegenerative disorders such as Alzheimer's disease. The brains of patients with Alzheimer's disease contain increased levels of lipid-peroxidation products such as 4-hydroxy-2-nonenal or acrolein, and enhanced lipid peroxidation can also be detected in cerebrospinal fluid and plasma from such patients. Recent research revealed that the interplay of transition metals, amyloid-beta peptide and lipid peroxidation might be responsible for increased oxidative stress and cell damage in this disease. In particular, the contrasting roles of amyloid-beta peptide, as a possible transition metal-chelating antioxidant for lipoproteins and a pro-oxidant when aggregated in brain tissue, has been the focus of discussion recently. In this context, lipid peroxidation has to be seen as an important part of the pathophysiological cascade in Alzheimer's disease, and its measurement in body fluids might serve as a therapy control for Alzheimer's disease and other neurodegenerative diseases.     

Sequencing the chimpanzee genome: insights into human evolution and disease

Large-scale sequencing of the chimpanzee genome is now imminent. Beyond the inherent fascination of comparing the sequence of the human genome with that of our closest living relative, this project is likely to yield tangible scientific benefits in two areas. First, the discovery of functionally important mutations that are specific to the human lineage offers a new path towards medical benefits. Second, chimpanzee-human comparisons are likely to yield molecular insights into how new biological characteristics evolve--findings that might be relevant throughout the tree of life.     

Lymphatic filariasis: new insights into an old disease

Lymphatic filariasis has afflicted people in the tropical areas of the world for thousands of years but even up to comparatively recent times it has been poorly understood and its importance under recognised. In the last 2 decades or so there has been a flurry of activity in filariasis research, which has provided new insights into the global problem of filariasis, the pathogenesis of filarial disease, diagnosis and control.     

Reaching new heights: insights into the genetics of human stature

Human height is a highly heritable, classic polygenic trait. Until recently, there had been limited success in identifying the specific genetic variants that explain normal variation of human height. The advent of large-scale genome-wide association studies, however, has led to dramatic progress. In the past 18 months, the first robust common variant associations were identified and there are now 44 loci known to influence normal variation of height. In this review, we summarize this exciting recent progress, discuss implicated biological pathways, the overlap with monogenic growth and skeletal dysplasia syndromes, links to disease and insights into the genetic architecture of this model polygenic trait. We also discuss the strong probability of finding several hundred more such loci in the near future.     

Allelic diversity in human developmental neurogenetics: insights into biology and disease

One of the biggest challenges in neuroscience is illuminating the architecture of developmental brain disorders, which include structural malformations of the brain and nerves, intellectual disability, epilepsy, and some psychiatric conditions like autism and potentially schizophrenia. Ongoing gene identification reveals a great diversity of genetic causes underlying abnormal brain development, illuminating new biochemical pathways often not suspected based on genetic studies in other organisms. Our greater understanding of genetic disease also shows the complexity of allelic diversity, in which distinct mutations in a given gene can cause a wide range of distinct diseases or other phenotypes. These diverse alleles not only provide a platform for discovery of critical protein-protein interactions in a genetic fashion, but also illuminate the likely genetic architecture of as yet poorly characterized neurological disorders.     

Replication of UV-damaged DNA: new insights into links between DNA polymerases, mutagenesis and human disease

The existence of homologous genes in diverse species is intriguing. A detailed comparison of the structure and function of gene families may provide important insights into gene regulation and evolution. An unproven assumption is that homologous genes have a common ancestor. During evolution, the original function of the ancestral gene might be retained in the different species which evolved along separate courses. In addition, new functions could have developed as the sequence began to diverge. This may also explain partly the presence of multipurpose genes, which have multiple functions at different stages of development and in different tissues. The Drosophila gene snail is a multipurpose gene; it has been demonstrated that snail is critical for mesoderm formation, for CNS development, and for wing cell fate determination. The related vertebrate Snail and Slug genes have also been proposed to participate in mesoderm formation, neural crest cell migration, carcinogenesis, and apoptosis. In this review, we will discuss the Snail/Slug family of regulators in species ranging from insect to human. We will present the protein structures, expression patterns, and functions based on molecular genetic analyses. We will also include the studies that helped to elucidate the molecular mechanisms of repression and the relationship between the conserved and divergent functions of these genes. Moreover, the studies may enable us to trace the evolution of this gene family.     

Pain and itch: insights into the neural circuits of aversive somatosensation in health and disease

Although pain and itch are distinct sensations, most noxious chemicals are not very specific to one sensation over the other, and recent discoveries are revealing that Trp channels function as transducers for both. A key difference between these sensations is that itch is initiated by irritation of the skin, whereas pain can be elicited from almost anywhere in the body; thus, itch may be encoded by the selective activation of specific subsets of neurons that are tuned to detect harmful stimuli at the surface and have specialized central connectivity that is specific to itch. Within the spinal cord, cross-modal inhibition between pain and itch may help sharpen the distinction between these sensations. Moreover, this idea that somatosensory modalities inhibit one another may be generalizable to other somatosensory subtypes, such as cold and hot. Importantly, just as there are inhibitory circuits in the dorsal horn that mediate cross-inhibition between modalities, it appears that there are also excitatory connections that can be unmasked upon injury or in disease, leading to abnormally elevated pain states such as allodynia. We are now beginning to understand some of this dorsal horn circuitry, and these discoveries are proving to be relevant for pathological conditions of chronic pain and itch.     

Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions

Ebola virus (EBOV) gained public notoriety in the last decade largely as a consequence of the highly publicized isolation of a new EBOV species in a suburb of Washington, DC, in 1989, together with the dramatic clinical presentation of EBOV infection and high case-fatality rate in Africa (near 90% in some outbreaks), and the unusual and striking morphology of the virus. Furthermore, there are no vaccines or effective therapies currently available. Progress in understanding the origins of the pathophysiological changes that make EBOV infections of humans so devastating has been slow, primarily because these viruses require special containment for safe research. However, an increasing understanding of the mechanisms of EBOV pathogenesis, facilitated by the development of new tools to elucidate critical regulatory elements in the viral life cycle, is providing new targets that can be exploited for therapeutic interventions. Notably, identifying factors triggering the haemorrhagic complications that characterise EBOV infections led to the development of a strategy to modulate coagulopathy; this therapeutic modality successfully mitigated the effects of EBOV haemorrhagic fever in nonhuman primates. This review summarises our current understanding of EBOV pathogenesis and discusses various approaches to therapeutic intervention based on our current understanding of how EBOV produces a lethal infection.     

The X-ray crystal structure of human beta-hexosaminidase B provides new insights into Sandhoff disease

Human lysosomal beta-hexosaminidases are dimeric enzymes composed of alpha and beta-chains, encoded by the genes HEXA and HEXB. They occur in three isoforms, the homodimeric hexosaminidases B (betabeta) and S (alphaalpha), and the heterodimeric hexosaminidase A (alphabeta), where dimerization is required for catalytic activity. Allelic variations in the HEXA and HEXB genes cause the fatal inborn errors of metabolism Tay-Sachs disease and Sandhoff disease, respectively. Here, we present the crystal structure of a complex of human beta-hexosaminidase B with a transition state analogue inhibitor at 2.3A resolution (pdb 1o7a). On the basis of this structure and previous studies on related enzymes, a retaining double-displacement mechanism for glycosyl hydrolysis by beta-hexosaminidase B is proposed. In the dimer structure, which is derived from an analysis of crystal packing, most of the mutations causing late-onset Sandhoff disease reside near the dimer interface and are proposed to interfere with correct dimer formation. The structure reported here is a valid template also for the dimeric structures of beta-hexosaminidase A and S.     

Comparative approaches to avian song system function: insights into auditory and motor processing

Many fundamental advances in our understanding of basic neural function have been made using bird song learning and performance as a model system. These advances have included a greater understanding of higher-order neural processing, developmental and hormonal influences on behavior, and the realization that neurogenesis plays an important role in normal adult brain function. The great diversity of passerine birds and song-related behaviors they exhibit suggest that oscine songbirds are ideally suited for comparative studies. While the comparative approach has been used successfully in the past to study song-related phenomena at anatomical and behavioral levels, it has been underutilized in addressing questions at the neurophysiological level. Most neurophysiological studies of songbird auditory and motor processing have been performed in one species, the zebra finch (Taeniopygia guttata). We present and compare neurophysiological studies we have performed in zebra finches and song sparrows (Melospiza melodia), species that differ markedly in their singing behavior and song repertoire characteristics. Interspecific similarities, and striking differences, in song neural processing are apparent. While preliminary, these data suggest that comparative neurophysiological studies of species carefully chosen for their vocal repertoire and singing behavior will contribute significantly to our understanding of vertebrate sensory and motor neural processing.     

Beyond pain in fibromyalgia: insights into the symptom of fatigue

Fatigue is a disabling, multifaceted symptom that is highly prevalent and stubbornly persistent. Although fatigue is a frequent complaint among patients with fibromyalgia, it has not received the same attention as pain. Reasons for this include lack of standardized nomenclature to communicate about fatigue, lack of evidence-based guidelines for fatigue assessment, and a deficiency in effective treatment strategies. Fatigue does not occur in isolation; rather, it is present concurrently in varying severity with other fibromyalgia symptoms such as chronic widespread pain, unrefreshing sleep, anxiety, depression, cognitive difficulties, and so on. Survey-based and preliminary mechanistic studies indicate that multiple symptoms feed into fatigue and it may be associated with a variety of physiological mechanisms. Therefore, fatigue assessment in clinical and research settings must consider this multi-dimensionality. While no clinical trial to date has specifically targeted fatigue, randomized controlled trials, systematic reviews, and meta-analyses indicate that treatment modalities studied in the context of other fibromyalgia symptoms could also improve fatigue. The Outcome Measures in Rheumatology (OMERACT) Fibromyalgia Working Group and the Patient Reported Outcomes Measurement Information System (PROMIS) have been instrumental in propelling the study of fatigue in fibromyalgia to the forefront. The ongoing efforts by PROMIS to develop a brief fibromyalgia-specific fatigue measure for use in clinical and research settings will help define fatigue, allow for better assessment, and advance our understanding of fatigue.     

Genetic determinants of human health span and life span: progress and new opportunities

We review three approaches to the genetic analysis of the biology and pathobiology of human aging. The first and so far the best-developed is the search for the biochemical genetic basis of varying susceptibilities to major geriatric disorders. These include a range of progeroid syndromes. Collectively, they tell us much about the genetics of health span. Given that the major risk factor for virtually all geriatric disorders is biological aging, they may also serve as markers for the study of intrinsic biological aging. The second approach seeks to identify allelic contributions to exceptionally long life spans. While linkage to a locus on Chromosome 4 has not been confirmed, association studies have revealed a number of significant polymorphisms that impact upon late-life diseases and life span. The third approach remains theoretical. It would require longitudinal studies of large numbers of middle-aged sib-pairs who are extremely discordant or concordant for their rates of decline in various physiological functions. We can conclude that there are great opportunities for research on the genetics of human aging, particularly given the huge fund of information on human biology and pathobiology, and the rapidly developing knowledge of the human genome.     

Crystal structures of human IPP isomerase: new insights into the catalytic mechanism

Type I isopentenyl diphosphate (IPP): dimethylally diphosphate (DMAPP) isomerase is an essential enzyme in human isoprenoid biosynthetic pathway. It catalyzes isomerization of the carbon-carbon double bonds in IPP and DMAPP, which are the basic building blocks for the subsequent biosynthesis. We have determined two crystal structures of human IPP isomerase I (hIPPI) under different crystallization conditions. High similarity between structures of human and Escherichia coli IPP isomerases proves the conserved catalytic mechanism. Unexpectedly, one of the hIPPI structures contains a natural substrate analog ethanol amine pyrophosphate (EAPP). Based on this structure, a water molecule is proposed to be the direct proton donor for IPP and different conformations of IPP and DMAPP bound in the enzyme are also proposed. In addition, structures of human IPPI show a flexible N-terminal alpha-helix covering the active pocket and blocking the entrance, which is absent in E. coli IPPI. Besides, the active site conformation is not the same in the two hIPPI structures. Such difference leads to a hypothesis that substrate binding induces conformational change in the active site. The inhibition mechanism of high Mn(2+) concentrations is also discussed.