Biomedical subjects

Harold J Morowitz

Publications and source records attributed to Harold J Morowitz.

3 recordsLinked to original sources

PubMed2006

Ancient genes in contemporary persistent microbial pathogens.

Autotrophs, the earliest prokaryotes, use CO(2) as the sole or the key source in the reductive citric acid cycle for carbon fixation. This pathway, also known as the reductive tricarboxylic acid (rTCA) cycle, has as its center the Krebs cycle running in the reductive direction, using reduced cofactors for energy. During the infection process, persistent pathogenic bacteria like Mycobacterium tuberculosis, Helicobacter pylori, and Salmonella typhi experience diverse and hostile environments both intracellularly (in macrophages) and extracellularly. M. tuberculosis, for example, must adapt to nutrient-deprived, hypoxic conditions in the granuloma. Genomic annotations reveal the presence of the key enzymes of the rTCA cycle--citrate lyase (Enzyme Commission number EC 4.1.3.6) and 2-oxoglutarate synthase (EC 1.2.7.3)--along with the rest of the TCA cycle enzymes. It is possible that there is a metabolic switch to anaerobic respiration in which a complete or a partial TCA cycle may operate in the reductive mode. This switch would both facilitate carbon fixation and restore the balance of oxidative and reductive reactions during environmental transitions, thus enabling the pathogen to survive, grow, and persist. Verification of enzyme function by biochemical investigations and validation of gene essentiality by knockout studies may reveal these enzymes to be rational drug targets for treatment of persistent microbial infections in mechanism-based drug discovery processes.

Archaea↗

PubMed2005

A mechanism for the association of amino acids with their codons and the origin of the genetic code.

The genetic code has certain regularities that have resisted mechanistic interpretation. These include strong correlations between the first base of codons and the precursor from which the encoded amino acid is synthesized and between the second base of codons and the hydrophobicity of the encoded amino acid. These regularities are even more striking in a projection of the modern code onto a simpler code consisting of doublet codons encoding a set of simple amino acids. These regularities can be explained if, before the emergence of macromolecules, simple amino acids were synthesized in covalent complexes of dinucleotides with alpha-keto acids originating from the reductive tricarboxylic acid cycle or reductive acetate pathway. The bases and phosphates of the dinucleotide are proposed to have enhanced the rates of synthetic reactions leading to amino acids in a small-molecule reaction network that preceded the RNA translation apparatus but created an association between amino acids and the first two bases of their codons that was retained when translation emerged later in evolution.

Amino Acids↗

PubMed2004

Universality in intermediary metabolism.

We analyze the stoichiometry, energetics, and reaction concentration dependence of the reductive tricarboxylic acid (rTCA) cycle as a universal and possibly primordial metabolic core. The rTCA reaction sequence is a network-autocatalytic cycle along the relaxation pathway for redox couples in nonequilibrium reducing environments, which provides starting organic compounds for the synthesis of all major classes of biomolecules. The concentration dependence of its reactions suggests it as a precellular bulk process. We propose that rTCA is statistically favored among competing redox relaxation pathways under early-earth conditions and that this feature drove its emergence and also accounts for its evolutionary robustness and universality. The ability to enhance the rate of core reactions creates an energetic basis for selection of subsequent layers of biological complexity.

Biomass↗