Biomedical subjects

J B Bonanno

Publications and source records attributed to J B Bonanno.

5 recordsLinked to original sources

PubMed2001

Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis.

X-ray structures of two enzymes in the sterol/isoprenoid biosynthesis pathway have been determined in a structural genomics pilot study. Mevalonate-5-diphosphate decarboxylase (MDD) is a single-domain alpha/beta protein that catalyzes the last of three sequential ATP-dependent reactions which convert mevalonate to isopentenyl diphosphate. Isopentenyl disphosphate isomerase (IDI) is an alpha/beta metalloenzyme that catalyzes interconversion of isopentenyl diphosphate and dimethylallyl diphosphate, which condense in the next step toward synthesis of sterols and a host of natural products. Homology modeling of related proteins and comparisons of the MDD and IDI structures with two other experimentally determined structures have shown that MDD is a member of the GHMP superfamily of small-molecule kinases and IDI is similar to the nudix hydrolases, which act on nucleotide diphosphatecontaining substrates. Structural models were produced for 379 proteins, encompassing a substantial fraction of both protein superfamilies. All three enzymes responsible for synthesis of isopentenyl diphosphate from mevalonate (mevalonate kinase, phosphomevalonate kinase, and MDD) share the same fold, catalyze phosphorylation of chemically similar substrates (MDD decarboxylation involves phosphorylation of mevalonate diphosphate), and seem to have evolved from a common ancestor. These structures and the structural models derived from them provide a framework for interpreting biochemical function and evolutionary relationships.

Amino Acid Sequence↗

PubMed2000

Structural studies of the [tris(imidazolyl)phosphine]metal nitrate complexes [[PimPrl,But]M(NO3)]+ (M = Co, Cu, Zn, Cd, Hg): comparison of nitrate-binding modes in synthetic analogues of carbonic anhydrase.

X-ray diffraction studies on a series of cationic divalent metal nitrate complexes supported by the tris(1-isopropyl-4-tert-butylimidazolyl)phosphine ligand, [[PimPri,But]M(NO3)]+ (M = Co, Cu, Zn, Cd, Hg), demonstrate that the nitrate ligand coordination mode is strongly dependent upon the metal. With the exception of that for the HgII derivative, the nitrate ligand coordination modes correlate with the activities of metal-substituted carbonic anhydrases, such that the only MII-carbonic anhydrases which exhibit significant activity, i.e., the Zn and Co species, are those for which the [[PimPri,But]M(NO3)]+ complexes possess strongly asymmetric nitrate ligands. This trend supports the notion that access to a unidentate, rather than a bidentate, bicarbonate intermediate may be a critical requirement for significant carbonic anhydrase activity. Interestingly, the nitrate coordination modes in the series of group 12 complexes, [[PimPri,But]M(NO3)]+ (M = Zn, Cd, Hg), do not exhibit a monotonic periodic trend: the bidenticity is greater for the cadmium complex than for either the zinc or mercury complexes. Since HgII-carbonic anhydrase is inactive, the correlation between nitrate coordination mode and enzyme activity is anomalous for the mercury complex. Therefore, it is suggested that the inactivity of HgII-carbonic anhydrase may be consequence of the reduced tendency of the mercury center in HgII-carbonic anhydrase to bind water.

Binding Sites↗

PubMed1999

Recognition of polyadenylate RNA by the poly(A)-binding protein.

The cocrystal structure of human poly(A)-binding protein (PABP) has been determined at 2.6 A resolution. PABP recognizes the 3' mRNA poly(A) tail and plays critical roles in eukaryotic translation initiation and mRNA stabilization/degradation. The minimal PABP used in this study consists of the N-terminal two RRM-type RNA-binding domains connected by a short linker (RRM1/2). These two RRMs form a continuous RNA-binding trough, lined by an antiparallel beta sheet backed by four alpha helices. The polyadenylate RNA adopts an extended conformation running the length of the molecular trough. Adenine recognition is primarily mediated by contacts with conserved residues found in the RNP motifs of the two RRMs. The convex dorsum of RRM1/2 displays a phylogenetically conserved hydrophobic/acidic portion, which may interact with translation initiation factors and regulatory proteins.

Adenine↗

PubMed1999

Structural genomics: beyond the human genome project.

With access to whole genome sequences for various organisms and imminent completion of the Human Genome Project, the entire process of discovery in molecular and cellular biology is poised to change. Massively parallel measurement strategies promise to revolutionize how we study and ultimately understand the complex biochemical circuitry responsible for controlling normal development, physiologic homeostasis and disease processes. This information explosion is also providing the foundation for an important new initiative in structural biology. We are about to embark on a program of high-throughput X-ray crystallography aimed at developing a comprehensive mechanistic understanding of normal and abnormal human and microbial physiology at the molecular level. We present the rationale for creation of a structural genomics initiative, recount the efforts of ongoing structural genomics pilot studies, and detail the lofty goals, technical challenges and pitfalls facing structural biologists.

Computational Biology↗

PubMed1984

HMO enrollment of Medicare recipients: an analysis of incentives and barriers.

Although there has been increased interest in use of the health maintenance organization (HMO) model to resolve a variety of problems relating to provision of health care to older individuals, less than 2 percent of Medicare beneficiaries are currently enrolled in HMOs. This paper examines both legislative and operational barriers to HMO enrollment of the elderly. Legislative reforms, HMO organizational structures, and marketing strategies thought to encourage enrollment of the elderly are discussed.

Aged↗