Homocysteine in Protein Structure/Function and Human Disease

Jakubowski, Hieronim

doi:10.1007/978-3-7091-1410-0

Cited by 42 publications

(52 citation statements)

References 320 publications

(793 reference statements)

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“…In addition, in the last few years, several pieces of evidence have indicated that protein unfolding and aggregation are crucial events leading to the formation of amyloid fibrils associated with a wide range of human pathologies. 47 For the first time, our results reveal that N-substitution of HTL can inhibit the aggregation of N-homocysteinylated albumin (see Figure 7 and Table 3). Analysis of a series of N-homocysteinylated albumin conjugates by gel electrophoresis demonstrated variable amounts of oligomer products of Hcy-HSA and CF 3 C(O)-Hcy-HSA, which were not present in the starting material, PFT-Hсy-HSA, and PFT-Hсy-HSA-Cy5.…”

Section: Discussionmentioning

confidence: 74%

“…47,58 Far-UV CD spectra of the homocysteinylated albumin differ strongly from those obtained from the unmodified albumin, suggesting that homocysteinylation results in a loss of the -helical content accompanied by an increase in the -sheet content (see Figure 6 and Table 2). On the other hand, our results clearly demonstrate that the fluorinated albumin conjugate retained most of the -helix present in the native protein.…”

Section: Discussionmentioning

confidence: 88%

“…47,66 However, sulfur compounds are very versatile in terms of their effects on the physiological environment. A small difference in their structure could result in great differences in their physiological functions and effects.…”

Section: Discussionmentioning

confidence: 99%

“…47,58 Modification, such as amidation or arylation, of Hcy residues in N-homocysteinylated albumin can affect protein conformation, as well as its ability to aggregate. Therefore, we tested the aggregation properties of the obtained fluorinated Hсy-HSA conjugates using gel retardation assay.…”

Section: Gel Retardation Assay Of Thiolactone-derived Homocystamide Amentioning

confidence: 99%

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Design of protein homocystamides with enhanced tumor uptake properties for 19F magnetic resonance imaging

Chubarov

Zakharova

Koval

et al. 2015

Bioorganic & Medicinal Chemistry

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Gel Retardation Assay Of Thiolactone-derived Homocystamide Amentioning

confidence: 99%

See 2 more Smart Citations

Design of protein homocystamides with enhanced tumor uptake properties for 19F magnetic resonance imaging

Chubarov

Zakharova

Koval

et al. 2015

Bioorganic & Medicinal Chemistry

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“…The accumulation of abnormal proteins in HHcy is known to be induced by Hcy-thiolactone, which accumulates in CBS-deficient patients, Cbs 2/2 mice (42,43), and hyperhomocysteinemic mouse brains (44). Hcythiolactone modifies protein lysine residues, causing protein damage that is toxic to cells (45)(46)(47). However, treatment of cultured cells with Hcy-thiolactone (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice

et al. 2016

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The molecular mechanisms leading to and responsible for age-related, sporadic Alzheimer's disease (AD) remain largely unknown. It is well documented that aging patients with elevated levels of the amino acid metabolite homocysteine (Hcy) are at high risk of developing AD. We investigated the impact of Hcy on molecular clearance pathways in mammalian cells, including in vitro cultured induced pluripotent stem cell-derived forebrain neurons and in vivo neurons in mouse brains. Exposure to Hcy resulted in up-regulation of the mechanistic target of rapamycin complex 1 (mTORC1) activity, one of the major kinases in cells that is tightly linked to anabolic and catabolic pathways. Hcy is sensed by a constitutive protein complex composed of leucyl-tRNA-synthetase and folliculin, which regulates mTOR tethering to lysosomal membranes. In hyperhomocysteinemic human cells and cystathionine β-synthase-deficient mouse brains, we find an acute and chronic inhibition of the molecular clearance of protein products resulting in a buildup of abnormal proteins, including β-amyloid and phospho-Tau. Formation of these protein aggregates leads to AD-like neurodegeneration. This pathology can be prevented by inhibition of mTORC1 or by induction of autophagy. We conclude that an increase of intracellular Hcy levels predisposes neurons to develop abnormal protein aggregates, which are hallmarks of AD and its associated onset and pathophysiology with age.-Khayati, K., Antikainen, H., Bonder, E. M., Weber, G. F., Kruger, W. D., Jakubowski, H., Dobrowolski, R. The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice.

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Aminoacyl‐tRNA synthetases and the evolution of coded peptide synthesis: the Thioester World

Jakubowski

2016

FEBS Letters

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Edited by Michael IbbaCoded peptide synthesis must have been preceded by a prebiotic stage, in which thioesters played key roles. Fossils of the Thioester World are found in extant aminoacyl-tRNA synthetases (AARSs). Indeed, studies of the editing function reveal that AARSs have a thiol-binding site in their catalytic modules. The thiol-binding site confers the ability to catalyze aminoacylc oenzyme A thioester synthesis and peptide bond formation. Genomic comparisons show that AARSs are structurally related to proteins involved in sulfur and coenzyme A metabolisms and peptide bond synthesis. These findings point to the origin of the amino acid activation and peptide bond synthesis functions in the Thioester World and suggest that the present-day AARSs had originated from ancestral forms that were involved in noncoded thioesterdependent peptide synthesis.

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Homocysteine in Protein Structure/Function and Human Disease

Cited by 42 publications

References 320 publications

Design of protein homocystamides with enhanced tumor uptake properties for 19F magnetic resonance imaging

Design of protein homocystamides with enhanced tumor uptake properties for 19F magnetic resonance imaging

The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice

Aminoacyl‐tRNA synthetases and the evolution of coded peptide synthesis: the Thioester World

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