The syndrome of inappropriate secretion of antidiuretic hormone

Erythropoietin (Epo), the hormone that stimulates red blood cell production, is synthesized in the kidney and liver in response to hypoxia. The human hepatoma cell line Hep3B regulates its production of Epo in a physiologic manner. Either hypoxia or cobalt chloride markedly increases expression of Epo mRNA as well as production of biologically active and immunologically distinct Epo protein. New protein synthesis is required before the induction of increased levels of hypoxia- or cobalt-induced Epo mRNA. Hypoxia, cobalt chloride, and nickel chloride appear to stimulate Epo production through a common pathway. The inhibition of Epo production at low partial pressures of oxygen by carbon monoxide provides evidence that a heme protein is integrally involved in the oxygen-sensing mechanism. This hypothesis is further supported by the finding that when heme synthesis is blocked, hypoxia-, cobalt-, and nickel-induced Epo production are all markedly inhibited. A model is proposed in which a ligand-dependent conformational change in a heme protein accounts for the mechanism by which hypoxia as well as cobalt and nickel stimulate the production of Epo.

https://science.sciencemag.org/content/sci/242/4884/1412.full.pdf

Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein

APEX is an engineered peroxidase that functions as an electron microscopy tag and a promiscuous labeling enzyme for live-cell proteomics. Because limited sensitivity precludes applications requiring low APEX expression, we used yeast-display evolution to improve its catalytic efficiency. APEX2 is far more active in cells, enabling the use of electron microscopy to resolve the submitochondrial localization of calcium uptake regulatory protein MICU1. APEX2 also permits superior enrichment of endogenous mitochondrial and endoplasmic reticulum membrane proteins.

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Directed evolution of APEX2 for electron microscopy and proximity labeling.

The heme synthesis and degradation pathways: role in oxidant sensitivity. Heme oxygenase has both pro- and antioxidant properties.

Gout

δ-Aminolevulinic Acid Synthetase I. STUDIES IN LIVER HOMOGENATES

δ-Aminolevulinic Acid Synthetase II. INDUCTION IN RAT LIVER

Acute intermittent porphyria. A clinical and biochemical study of 46 patients.

Allylisopropylacetamide (AIA), when administered to rats, induces high levels of hepatic mitochondrial δ-aminolevulinic acid synthetase (ALA synthetase). The activity of this enzyme can be quantitated in porphyric rat liver, since the freshly prepared mitochondria from porphyric rat liver are permeable to succinyl-coenzyme A and do not have high deacylase activity. Administration of carbohydrate to rats markedly inhibits the induction of ALA synthetase by AIA. Since ALA synthetase is thought to be the rate controlling enzyme in hepatic porphyrin biosynthesis, diet is a regulatory factor in hepatic porphyrin synthesis in porphyria. The previously observed effects of diet on porphyrin precursor excretion in both experimental and human acute intermittent porphyria are best explained by the effect of diet on the hepatic ALA synthetase level. The application of the theory of “catabolite repression” to the present findings is discussed.

The effect of carbohydrate feeding on the induction of δ-aminolevulinic acid synthetase

In a patient with a severe attack of acute intermittent porphyria, hematin given intravenously caused marked diminution of serum δ-aminolevulinic acid and porphobilinogen. The decline of aminolevulinate was more rapid than that of porphobilinoge. After 2 days of hematin administration, about 5 days were required for δ-aminolevulinic acid, and 11 days for porphobilinogen to return to the concentrations that were detected before treatment. Urinary excretion of both compounds also decreased after hematin administration. Considerable amounts of porphobilinogen were also found in the cerebrospinal fluid of the patient.

http://www.pnas.org/content/68/11/2725.full.pdf

Donald P. Tschudy

Papers

δ-Aminolevulinic Acid Synthetase I. STUDIES IN LIVER HOMOGENATES

δ-Aminolevulinic Acid Synthetase II. INDUCTION IN RAT LIVER

Acute intermittent porphyria. A clinical and biochemical study of 46 patients.

The effect of carbohydrate feeding on the induction of δ-aminolevulinic acid synthetase

Repression of the Overproduction of Porphyrin Precursors in Acute Intermittent Porphyria by Intravenous Infusions of Hematin