Recognition of structurally diverse substrates by type II 3-hydroxyacyl-CoA dehydrogenase (HADH II)/Amyloid-β binding alcohol dehydrogenase (ABAD)

2000 ◽  
Vol 303 (2) ◽  
pp. 311-327 ◽  
Author(s):  
A.J Powell ◽  
J.A Read ◽  
M.J Banfield ◽  
F Gunn-Moore ◽  
S.D Yan ◽  
...  
Keyword(s):  
Alcohol Dehydrogenase ◽  
Amyloid Β ◽  
Type Ii ◽  
Hydroxyacyl Coa Dehydrogenase

scholarly journals Intrinsic alcohol dehydrogenase and hydroxysteroid dehydrogenase activities of human mitochondrial short-chain L-3-hydroxyacyl-CoA dehydrogenase

1999 ◽  
Vol 345 (1) ◽  
pp. 139-143 ◽  
Author(s):  
Xue-Ying HE ◽  
Ying-Zi YANG ◽  
Horst SCHULZ ◽  
Song-Yu YANG
Keyword(s):  
Alcohol Dehydrogenase ◽  
Catalytic Properties ◽  
Amyloid Β ◽  
Hydroxysteroid Dehydrogenase ◽  
Amino Acid Sequences ◽  
Short Chain ◽  
Amyloid Β Peptide ◽  
Kinetic Measurements ◽  
Hydroxyacyl Coa Dehydrogenase ◽  
Adh Activity

The alcohol dehydrogenase (ADH) activity of human short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) has been characterized kinetically. The kcat of the purified enzyme was estimated to be 2.2 min-1, with apparent Km values of 280 mM and 22μM for 2-propanol and NAD+, respectively. The kcat of the ADH activity was three orders of magnitude less than the L-3-hydroxyacyl-CoA dehydrogenase activity but was comparable with that of the enzyme's hydroxysteroid dehydrogenase (HSD) activity for oxidizing 17β-oestradiol [He, Merz, Mehta, Schulz and Yang (1999) J. Biol. Chem. 274, 15014-15019]. However, the kcat values of intrinsic ADH and HSD activities of human SCHAD were found to be two orders of magnitude less than those reported for endoplasmic-reticulum-associated amyloid β-peptide-binding protein (ERAB) [Yan, Shi, Zhu, Fu, Zhu, Zhu, Gibson, Stern, Collison, Al-Mohanna et al. (1999) J. Biol. Chem. 274, 2145-2156]. Since human SCHAD and ERAB apparently possess identical amino acid sequences, their catalytic properties should be identical. The recombinant SCHAD has been confirmed to be the right gene product and not a mutant variant. Steady-state kinetic measurements and quantitative analyses reveal that assay conditions such as pH and concentrations of coenzyme and substrate do not account for the kinetic differences reported for ERAB and SCHAD. Rather problematic experimental procedures appear to be responsible for the unrealistically high catalytic rate constants of ERAB. Eliminating the confusion surrounding the catalytic properties of this important multifunctional enzyme paves the way for exploring its role(s) in the pathogenesis of Alzheimer's disease.

scholarly journals scully, an Essential Gene of Drosophila, is Homologous to Mammalian Mitochondrial Type II l-3-hydroxyacyl-CoA Dehydrogenase/Amyloid-β Peptide-binding Protein

1998 ◽  
Vol 141 (4) ◽  
pp. 1009-1017 ◽  
Author(s):  
Laura Torroja ◽  
Daniel Ortuño-Sahagún ◽  
Alberto Ferrús ◽  
Barbara Hämmerle ◽  
Julio A. Barbas
Keyword(s):  
Germ Line ◽  
Essential Gene ◽  
Amyloid Β ◽  
Single Amino Acid ◽  
Amyloid Β Peptide ◽  
Type Ii ◽  
Phenotypic Analysis ◽  
Lipid Inclusions ◽  
Hydroxyacyl Coa Dehydrogenase

The characterization of scully, an essential gene of Drosophila with phenocritical phases at embryonic and pupal stages, shows its extensive homology with vertebrate type II l-3-hydroxyacyl-CoA dehydrogenase/ERAB. Genomic rescue demonstrates that four different lethal mutations are scu alleles, the molecular nature of which has been established. One of them, scu3127, generates a nonfunctional truncated product. scu4058 also produces a truncated protein, but it contains most of the known functional domains of the enzyme. The other two mutations, scu174 and scuS152, correspond to single amino acid changes. The expression of scully mRNA is general to many tissues including the CNS; however, it is highest in both embryonic gonadal primordia and mature ovaries and testes. Consistent with this pattern, the phenotypic analysis suggests a role for scully in germ line formation: mutant testis are reduced in size and devoid of maturing sperm, and mutant ovarioles are not able to produce viable eggs. Ultrastructural analysis of mutant spermatocytes reveals the presence of cytoplasmic lipid inclusions and scarce mitochondria. In addition, mutant photoreceptors contain morphologically aberrant mitochondria and large multilayered accumulations of membranous material. Some of these phenotypes are very similar to those present in human pathologies caused by β-oxidation disorders.

scholarly journals Age-dependent formation of TMEM106B amyloid filaments in human brain

2021 ◽  
Author(s):  
Manuel Schweighauser ◽  
Diana Arseni ◽  
Melissa Huang ◽  
Sofia Lövestam ◽  
Yang Shi ◽  
...  
Keyword(s):  
Human Brain ◽  
Transmembrane Protein ◽  
Amyloid Β ◽  
Dependent Manner ◽  
Type Ii ◽  
Western Blots ◽  
Normal Individuals ◽  
Age Dependent ◽  
Neurologically Normal ◽  
Filamentous Inclusions

Many age-dependent neurodegenerative diseases, like Alzheimer's and Parkinson's, are characterised by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-β (Aβ), α-synuclein and TDP-43 are the most common. Here, we used electron cryo-microscopy (cryo-EM) structure determination to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in the human brain. We solved cryo-EM structures of TMEM106B filaments from the brains of 22 individuals with neurodegenerative conditions, including sporadic and inherited tauopathies, Aβ-amyloidoses, synucleinopathies and TDP-43opathies, as well as from the brains of two neurologically normal individuals. We observed three different TMEM106B folds, with no clear relationship between folds and diseases. The presence of TMEM106B filaments correlated with that of a 29 kDa sarkosyl-insoluble fragment of the protein on Western blots. The presence of TMEM106B filaments in the brains of older, but not younger, neurologically normal individuals indicates that they form in an age-dependent manner.

Computational optimization of AG18051 inhibitor for amyloid-β binding alcohol dehydrogenase enzyme

2008 ◽  
Vol 108 (11) ◽  
pp. 1982-1991 ◽  
Author(s):  
Alexandra T. Marques ◽  
Agostinho Antunes ◽  
Pedro A. Fernandes ◽  
Maria J. Ramos
Keyword(s):  
Alcohol Dehydrogenase ◽  
Amyloid Β ◽  
Computational Optimization ◽  
Dehydrogenase Enzyme

Abstract P243: A New Type 2 Diabetic Rat Model That is Associated with Cognitive Impairment in Aging

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Wenshan Lv ◽  
Hongwei Yu ◽  
Longyang Li ◽  
Christine Taylor ◽  
Ezekiel Gonzalez-Fernandez ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Rat Model ◽  
Amyloid Β ◽  
Diabetic Rat ◽  
Type Ii ◽  
Sd Rats ◽  
Increased Risk ◽  
New Type ◽  
Diabetic Rat Model ◽  
Cerebral Vascular

Alzheimer’s disease (AD) is an incurable neurodegenerative disease and the most common form of dementia, and AD and type II diabetes (DM II) are two of the most common diseases of aging. Numerous studies demonstrate DM II with increased risk for dementia, however, the mechanisms linking DM II and AD have not been fully elucidated. There is increasing evidence suggesting that cerebral vascular dysfunction plays an important role in the development of AD. T2DN rat is a DM II rat model that exhibits diabetic nephropathy. The present study examines whether aged T2DN rat is associated with cognitive impairment, and whether autoregulation of cerebral blood flow (CBF) is impaired that contributes to AD. The levels of glucose (422 ± 32 vs. 94 ± 3 mg/dL) and glycated hemoglobin (HbA 1c , 11.5 ± 0.2 vs. 4.3 ± 0.1%) were higher in 12-18 months old T2DN than in age matched SD control rats. CBF rose by 137 ± 15% and 36 ± 5%, respectively, in T2DN and SD rats when MAP was increased from 100 to 180 mmHg. Aged T2DN rats exhibited BBB leakage and “AD” like cerebral vascular remodeling. The expression of Amyloid β 42 (Aβ 4 2 ), p-tau (S416), GFAP and IL-1 beta were significantly higher in the brains of T2DN vs. SD rats. T2DN rats also exhibited learning and memory dysfunction as the short term (2-hour; T2DN 96 ± 12 vs. SD 13 ± 3 seconds) and long term (24-hour; T2DN 105 ± 15 vs. SD 8 ± 2 seconds) latency of escape were longer in an eight-arm water maze test, and spent less time in the target arm 48 hours after training (T2DN 3.4 ± 2.6 vs. SD 45.0 ± 1.7%). These findings indicate that T2DN is a new type II diabetic rat model. Elderly T2DN rat is associated with an impaired autoregulation of CBF, glial activation and inflammation which may contribute to the development of cognitive impairment and AD.

scholarly journals Cryo-EM Structures of Amyloid-β 42 Filaments from Human Brain

2021 ◽  
Author(s):  
Yang ` Yang ◽  
Diana Arseni ◽  
Wenjuan Zhang ◽  
Melissa Huang ◽  
Sofia Lövestam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Amyloid Β ◽  
Imaging Agents ◽  
Type I ◽  
Type Ii ◽  
Sporadic Alzheimer’S Disease ◽  
Filament Assembly

Filament assembly of amyloid-β peptides ending at residue 42 (Aβ42) is a central event in Alzheimer's disease. We report the cryo-EM structures of Aβ42 filaments from brain. Two structurally related S-shaped protofilament folds give rise to two types of filaments. Type I filaments were found mostly in the brains of individuals with sporadic Alzheimer's disease and Type II filaments in individuals with familial Alzheimer's disease and other conditions. The structures of Aβ42 filaments from brain differ from those of filaments assembled in vitro. By contrast, in App NL-F knock-in mice, Aβ42 deposits were made of Type II filaments. Knowledge of Aβ42 filament structures from human brain may lead to the development of inhibitors of assembly and improved imaging agents.

scholarly journals Ovariectomy increases neuronal amyloid-β binding alcohol dehydrogenase level in the mouse hippocampus

2008 ◽  
Vol 52 (7) ◽  
pp. 1358-1364 ◽  
Author(s):  
Emiko Fukuzaki ◽  
Kazuhiro Takuma ◽  
Yoko Funatsu ◽  
Yukiko Himeno ◽  
Yuko Kitahara ◽  
...  
Keyword(s):  
Alcohol Dehydrogenase ◽  
Amyloid Β ◽  
Mouse Hippocampus
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