The chemistry of Alzheimer’s disease is largely centred on the amyloid β-peptide, its formation, structure, and interactions with metals, membranes, proteins and other species. This critical review summarizes the current state of knowledge (252 references).

The chemistry of Alzheimer's disease.

Integrated view on 17beta-hydroxysteroid dehydrogenases.

Structure and function of human 17beta-hydroxysteroid dehydrogenases.

17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) are enzymes that are responsible for reduction or oxidation of hormones, fatty acids and bile acids in vivo, regulating the amount of the active form that is available to bind to its cognate receptor. All require NAD(P)(H) for activity. Fifteen 17beta-HSDs have been identified to date, and with one exception, 17beta-HSD type 5 (17beta-HSD5), an aldo-keto reductase, they are all short-chain dehydrogenases/reductases, although overall homology between the enzymes is low. Although named as 17beta-HSDs, reflecting the major redox activity at the 17beta-position of the steroid, the activities of these 15 enzymes vary, with several of the 17beta-HSDs able to reduce and/or oxidise multiple substrates at various positions. These activities are involved in the progression of a number of diseases, including those related to steroid metabolism. Despite the success of inhibitors of steroidogenic enzymes in the clinic, such as those of aromatase and steroid sulphatase, the development of inhibitors of 17beta-HSDs is at a relatively early stage, as at present none have yet reached clinical trials. However, many groups are now working on inhibitors specific for several of these enzymes for the treatment of steroid-dependent diseases, including breast and prostate cancer, and endometriosis, with demonstrable efficacy in in vivo disease models. In this review, the recent advances in the validation of these enzymes as targets for the treatment of these diseases, with emphasis on 17beta-HSD1, 3 and 5, the development of specific inhibitors, the models used for their evaluation, and their progress towards the clinic will be discussed.

/pdf/design-and-validation-of-specific-inhibitors-of-17b-3350gbbyg2.pdf

Design and validation of specific inhibitors of 17β-hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid β-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. HAD has a preference for medium chain substrates, whereas short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) acts on a wide spectrum of substrates, including steroids, cholic acids, and fatty acids, with a preference for short chain methyl-branched acyl-CoAs. Therefore, HAD should not be referred to as SCHAD. SCHAD is not a member of the HAD family, but instead, belongs to the short chain dehydrogenase/reductase superfamily. Previously reported cases of SCHAD deficiency are due to an inherited HAD deficiency. SCHAD, also known as 17β-hydroxysteroid dehydrogenase type 10, is important in brain development and aging. Abnormal levels of SCHAD in certain brain regions may contribute to the pathogenesis of some neural disorders. The human SCHAD gene and its protein product, SCHAD, are potential targets for intervention in conditions, such as Alzheimer's disease, Parkinson's disease, and an X-linked mental retardation, that may arise from the impaired degradation of branched chain fatty acid and isoleucine.

3‐Hydroxyacyl‐CoA dehydrogenase and short chain 3‐hydroxyacyl‐CoA dehydrogenase in human health and disease

The identification, isolation and modification of human ERAB or HADH2 is described. A crystal structure of ERAB or HADH2 is described which may be used in the discovery, identification and characterization of inhibitors or modulators of ERAB or HADH2. This structure provides a three-dimensional description of binding sites of ERAB or HADH2 for structure-based design of inhibitors or modulators thereof as therapeutic agents, for example in the treatment of Alzheimer's disease).

Peptide mutant of human ERAB/HADH2, its X-ray crystal structure, and materials and method for identification of inhibitors thereof

Pyrazole compounds represented by the formula (I), are described. The pyrazole compounds and pharmaceutical compositions containing them may be used in inhibiting ERAB or HADH2 activity and in treating ERAB, HADH2 or amyloid-β mediated diseases and conditions.

Pyrazole compounds, pharmaceutical compositions, and methods for modulating or inhibiting erab or hadh2 activity

Crystal structure of human ABAD/HSD10 with a bound inhibitor: implications for design of Alzheimer's disease therapeutics.

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Peptide mutant of human ERAB/HADH2, its X-ray crystal structure, and materials and method for identification of inhibitors thereof

Pyrazole compounds, pharmaceutical compositions, and methods for modulating or inhibiting erab or hadh2 activity

Crystal structure of human ABAD/HSD10 with a bound inhibitor: implications for design of Alzheimer's disease therapeutics.