Sinkkihomeostaasin geeniperheistä ZNT ja ZIP. Perhe ZNT, 10 jäsentä.

Kaksi proteiiniperhettä SLC30A (ZNT) ja SLC39A (ZIP) osallistuvat sinkin homeostaasiin.Sinkillä on merkitys glukoosiaineenvaihdunnalle.
https://pubmed.ncbi.nlm.nih.gov/29372370/?from_term=SLC30A+family&from_pos=1

ZNT geeni perhe

(1) Zinc Transporter 1, SLC30, ZNT(1q32.3)

Sinkinpuute tyyppi. Acrodermatitis enteropathica.

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A1&keywords=ZNT1 GeneCards Summary for SLC30A1 Gene

SLC30A1 (Solute Carrier Family 30 Member 1) is a Protein Coding gene. Diseases associated with SLC30A1 include Epidermodysplasia Verruciformis 1 and Acrodermatitis Enteropathica, Zinc-Deficiency Type. Among its related pathways are Mineral absorption and Metal ion SLC transporters. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity and calcium channel inhibitor activity. An important paralog of this gene is SLC30A10. UniProtKB/Swiss-Prot Summary for SLC30A1 Gene: May be involved in zinc transport out of the cell. ZNT1_HUMAN,Q9Y6M5

(2) Zinc transporter 2 (1p36.11) , ZNT2, SLC30A2, TNZD, PP12488.

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A2&keywords=ZNT2

(Sinkin erittyminen äidinmaitoon. Sinkinpuute tyyppi).

The protein encoded by this gene is a zinc transporter that acts as a homodimer. The encoded protein plays a role in secreting zinc into breast milk. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

SLC30A2 (Solute Carrier Family 30 Member 2) is a Protein Coding gene. Diseases associated with SLC30A2 include Zinc Deficiency, Transient Neonatal and Acrodermatitis Enteropathica, Zinc-Deficiency Type. Among its related pathways are Metal ion SLC transporters and Transport of glucose and other sugars, bile salts and organic acids, metal ions and amine compounds. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity. An important paralog of this gene is SLC30A3.

(3) ZNT3, SCL30A3 ( 2p23.3)

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A3&keywords=ZNT3

GeneCards Summary for SLC30A3 Gene

SLC30A3 (Solute Carrier Family 30 Member 3) is a Protein Coding gene. Diseases associated with SLC30A3 include Hyperekplexia. Among its related pathways are Metal ion SLC transporters and Transport of glucose and other sugars, bile salts and organic acids, metal ions and amine compounds. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity and zinc-transporting ATPase activity. An important paralog of this gene is SLC30A2. UniProtKB/Swiss-Prot Summary for SLC30A3 Gene Involved in accumulation of zinc in synaptic vesicles. ZNT3_HUMAN,Q99726

(4) ZNT4 , SLC30A4(15q21.1)

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A4&keywords=ZNT4 Zinc is the second most abundant trace metal in the human body. It is an essential element, serving both a structural role, as in the formation of zinc fingers in DNA-binding proteins, and a catalytic role in metalloenzymes, such as pancreatic carboxypeptidases (e.g., MIM 114852), alkaline phosphatases (e.g., MIM 171760), various dehydrogenases, and superoxide dismutases (e.g., MIM 147450). SLC30A4, or ZNT4, belongs to the ZNT family of zinc transporters. ZNTs are involved in transporting zinc out of the cytoplasm and have similar structures, consisting of 6 transmembrane domains and a histidine-rich cytoplasmic loop (Huang and Gitschier, 1997 [PubMed 9354792]).[supplied by OMIM, Mar 2008] GeneCards Summary for SLC30A4 Gene SLC30A4 (Solute Carrier Family 30 Member 4) is a Protein Coding gene. Diseases associated with SLC30A4 include Acrodermatitis Enteropathica, Zinc-Deficiency Type and Acrodermatitis. Among its related pathways are Metal ion SLC transporters. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity and zinc ion transmembrane transporter activity. An important paralog of this gene is SLC30A2. Probably involved in zinc transport out of the cytoplasm, maybe by sequestration into an intracellular compartment. ZNT4_HUMAN,O14863

(5) ZNT5 (SLC30A5) (5q13.1-q13.29 , ZNTL1, HZTL1

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A5&keywords=ZNT5 Entrez Gene Summary for SLC30A5 Gene This gene encodes a member of the SLC30A/ZnT family of zinc transporter proteins. ZnT proteins mediate both cellular zinc efflux and zinc sequestration into membrane-bound organelles. The encoded protein plays a role in the early secretory pathway as a heterodimer with zinc transporter 6, and may also regulate zinc sequestration into secretory granules of pancreatic beta cells. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 19. [provided by RefSeq, Oct 2011] GeneCards Summary for SLC30A5 Gene SLC30A5 (Solute Carrier Family 30 Member 5) is a Protein Coding gene. Diseases associated with SLC30A5 include Acrodermatitis Enteropathica, Zinc-Deficiency Type and Nonsyndromic Deafness. Among its related pathways are Metal ion SLC transporters and Peptide hormone metabolism. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity and zinc ion transmembrane transporter activity. An important paralog of this gene is SLC30A7. UniProtKB/Swiss-Prot Summary for SLC30A5 Gene Functions as a zinc transporter. May be a transporter of zinc into beta cells in order to form insulin crystals. Partly regulates cellular zinc homeostasis. Required with ZNT7 for the activation of zinc-requiring enzymes, alkaline phosphatases (ALPs). Transports zinc into the lumens of the Golgi apparatus and vesicular compartments where ALPs locate, thus, converting apoALPs to holoALPs. Required with ZNT6 and ZNT7 for the activation of TNAP. ZNT5_HUMAN,Q8TAD4

(6) ZNT6, SLC30A6, (2p22.3), MST103, MSTP103.

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A6&keywords=ZNT6 Entrez Gene Summary for SLC30A6 Gene This gene encodes a member of a family of proteins that function as zinc transporters. This protein can regulate subcellular levels of zinc in the Golgi and vesicles. Expression of this gene is altered in the Alzheimer's disease brain plaques. [provided by RefSeq, Aug 2016] GeneCards Summary for SLC30A6 Gene SLC30A6 (Solute Carrier Family 30 Member 6) is a Protein Coding gene. Diseases associated with SLC30A6 include Alzheimer Disease and Myasthenic Syndrome, Congenital, 5. Among its related pathways are Metal ion SLC transporters and Peptide hormone metabolism. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity and zinc ion transmembrane transporter activity. An important paralog of this gene is SLC30A5. UniProtKB/Swiss-Prot Summary for SLC30A6 Gene Zinc-efflux transporter which allocates the cytoplasmic zinc to the trans-Golgi network (TGN) as well as the vesicular compartment. ZNT6_HUMAN,Q6NXT4

(7) ZNT7, SLC30A7 . Zinc transporter like 2, ZNTL2.

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A7&keywords=ZNT7Entrez Gene Summary for SLC30A7 Gene. Zinc functions as a cofactor for numerous enzymes, nuclear factors, and hormones and as an intra- and intercellular signal ion. Members of the zinc transporter (ZNT)/SLC30 subfamily of the cation diffusion facilitator family, such as SLC30A7, permit cellular efflux of zinc (Seve et al., 2004 [PubMed 15154973]).[supplied by OMIM, Mar 2008] GeneCards Summary for SLC30A7 Gene

SLC30A7 (Solute Carrier Family 30 Member 7) is a Protein Coding gene. Diseases associated with SLC30A7 include Joubert Syndrome 1 and Acrodermatitis Enteropathica, Zinc-Deficiency Type. Among its related pathways are Metal ion SLC transporters and Peptide hormone metabolism. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity. An important paralog of this gene is SLC30A5. UniProtKB/Swiss-Prot Summary for SLC30A7 Gene Seems to facilitate zinc transport from the cytoplasm into the Golgi apparatus. Partly regulates cellular zinc homeostasis. Required with ZNT5 for the activation of zinc-requiring enzymes, alkaline phosphatases (ALPs). Transports zinc into the lumens of the Golgi apparatus and the vesicular compartments where ALPs locate, thus, converting apoALPs to holoALPs. Required with ZNT5 and ZNT6 for the activation of TNAP (By similarity). ZNT7_HUMAN,Q8NEW0
 

(8), ZNT8, SLC30A8, (8q24.11)

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC30A8&keywords=ZNT8 Entrez Gene Summary for SLC30A8 Gene. The protein encoded by this gene is a zinc efflux transporter involved in the accumulation of zinc in intracellular vesicles. This gene is expressed at a high level only in the pancreas, particularly in islets of Langerhans. The encoded protein colocalizes with insulin in the secretory pathway granules of the insulin-secreting INS-1 cells. Allelic variants of this gene exist that confer susceptibility to diabetes mellitus, noninsulin-dependent (NIDDM). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]. GeneCards Summary for SLC30A8 Gene. SLC30A8 (Solute Carrier Family 30 Member 8) is a Protein Coding gene. Diseases associated with SLC30A8 include Diabetes Mellitus, Noninsulin-Dependent and Diabetes Mellitus. Among its related pathways are Metal ion SLC transporters and Peptide hormone metabolism. Gene Ontology (GO) annotations related to this gene include protein homodimerization activity and zinc ion transmembrane transporter activity. An important paralog of this gene is SLC30A2. UniProtKB/Swiss-Prot Summary for SLC30A8 Gene. Facilitates the accumulation of zinc from the cytoplasm into intracellular vesicles, being a zinc-efflux transporter. May be a major component for providing zinc to insulin maturation and/or storage processes in insulin-secreting pancreatic beta-cells. ZNT8_HUMAN,Q8IWU4

(9) ZNT9, SLC30A9.(4p13), GRIP1- dependent Nuclear Receptor Coactivator, GAC63, Chromosome4 OREF1, BILAPES, HuEL.
 GeneCards Summary for SLC30A9 Gene

SLC30A9 (Solute Carrier Family 30 Member 9) is a Protein Coding gene. Diseases associated with SLC30A9 include Birk-Landau-Perez Syndrome and Hemochromatosis, Type 5. Among its related pathways are Metal ion SLC transporters. Gene Ontology (GO) annotations related to this gene include DNA-binding transcription factor activity and nuclear receptor transcription coactivator activity. UniProtKB/Swiss-Prot Summary for SLC30A9 Gene Acts as a zinc transporter involved in intracellular zinc homeostasis (PubMed:28334855). Functions as a secondary coactivator for nuclear receptors by cooperating with p160 coactivators subtypes. Plays a role in transcriptional activation of Wnt-responsive genes (By similarity). ZNT9_HUMAN,Q6PML9 Quaternary structure: Interacts with GRIP1, ESR1 and AR.

(10) ZNT10, SLC30A10, (1q41), Manganese Transporter SLC30 A19, HMNDYT1, HMDPC, ZRC1, ZNT8.
Entrez Gene Summary for SLC30A10 Gene This gene is highly expressed in the liver and is inducible by manganese. Its protein product appears to be critical in maintaining manganese levels, and has higher specificity for manganese than zinc. Loss of function mutations appear to result in a pleomorphic phenotype, including dystonia and adult-onset parkinsonism. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Mar 2012]GeneCards Summary for SLC30A10 Gene SLC30A10 (Solute Carrier Family 30 Member 10) is a Protein Coding gene. Diseases associated with SLC30A10 include Hypermanganesemia With Dystonia 1 and Hypermanganesemia With Dystonia. Among its related pathways are Metal ion SLC transporters. Gene Ontology (GO) annotations related to this gene include cation transmembrane transporter activity. An important paralog of this gene is SLC30A1. UniProtKB/Swiss-Prot Summary for SLC30A10 Gene. Plays a pivotal role in manganese transport. Manganese is an essential cation for the function of several enzymes, including some crucially important for the metabolism of neurotransmitters and other neuronal metabolic pathways. However, elevated levels of manganese are cytotoxic and induce oxidative stress, mitochondrial dysfunction and apoptosis. Acts as manganese efflux transporter and confers protection against manganese-induced cell death (PubMed:22341972, PubMed:22341971, PubMed:25319704, PubMed:27226609, PubMed:27307044). Also acts as zinc transporter involved in zinc homeostasis. Seems to mediate zinc transport into early endosomes and recycling endosomes to prevent zinc toxicity; the function may be regulated by heterodimerization with other zinc transporters of the SLC30A subfamily. The SLC30A3:SLC30A10 heterodimer is involved in zinc transport-dependent regulation of the EGFR/ERK transduction pathway in endosomes. May be involved in regulation of zinc-dependent senescence of vascular smooth muscle cells (PubMed:22706290, PubMed:22427991, PubMed:26728129). ZNT10_HUMAN,Q6XR72 Protein attributes for SLC30A10 Gene Size: 485 amino acids , Molecular mass: 52684 Da . Quaternary structure: Forms homodimers. Forms heterodimers and high-molecular weight oligomers with SLC30A3, SLC30A2 and SLC30A4; heterodimerization is mediated by covalent-bound tyrosine residues and occurs probably in a tissue-specific manner. Miscellaneous: [Isoform 2]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. SequenceCaution: Sequence=AAP44332.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in position 427.; Evidence={ECO:0000305};

(11) ZNT tästä eteenpäin ei löydy geenejä tällä perhenimellä  SLC30A.
9.6. 2020 ZNT perheen geeneistä Gene Cards lähteestä. hakusanana  ZNT , numerot 1-10 tai  SCL30A numerot 1-10.
Klo 12:02.

HYPERGLYCEMIA , ACE2, haku, 44 vastausta., 10 ensimmäistä.

44 results

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1

Hyperglycemia, hydroxychloroquine, and the COVID-19 pandemic.

Brufsky A. J Med Virol. 2020 Apr 15. doi: 10.1002/jmv.25887. Online ahead of print. PMID: 32293710 Review.

Coronavirus disease-2019 (COVID-19) infection and its severity can be explained by the concentration of glycosylated severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral particles in the lung epithelium, the concentration of glycosylated angiotensin-converting enzyme receptor 2 (ACE2) in the lung epithelium, and the degree and control of the pulmonary immune response to the SARS-CoV-2 spike protein at approximately day 8 to 10 after symptom onset, which may be related to both. Binding of ACE2 by SARS-CoV-2 in COVID-19 also suggests that prolonged uncontrolled hyperglycemia, and not just a history of diabetes mellitus, may be important in the pathogenesis of the disease. It is tempting to consider that the same mechanism acts in COVID-19 as in SARS, where an overactive macrophage M1 inflammatory response, as neutralizing antibodies to the SARS-CoV-2 spike protein form at day 7 to 10, results in acute respiratory distress syndrome (ARDS) in susceptible patients. It also allows consideration of agents, such as hydroxychloroquine, which may interfere with this overly brisk macrophage inflammatory response and perhaps influence the course of the disease, in particular, those that blunt but do not completely abrogate the M1 to M2 balance in macrophage polarization, as well as viral load, which in SARS appears to be temporally related to the onset of ARDS. 

2.

ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity.

Patel VB, Mori J, McLean BA, Basu R, Das SK, Ramprasath T, Parajuli N, Penninger JM, Grant MB, Lopaschuk GD, Oudit GY. Diabetes. 2016 Jan;65(1):85-95. doi: 10.2337/db15-0399. Epub 2015 Jul 29. PMID: 26224885 Free PMC article.

Obesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance.

© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. 

3. 

Activation of ACE2/angiotensin (1-7) attenuates pancreatic β cell dedifferentiation in a high-fat-diet mouse model.

Xuan X, Gao F, Ma X, Huang C, Wang Y, Deng H, Wang S, Li W, Yuan L. Metabolism. 2018 Apr;81:83-96. doi: 10.1016/j.metabol.2017.12.003. Epub 2017 Dec 7. PMID: 29225087

OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2) has been identified in pancreatic islets and can preserve β cells. In this study, we aimed to examine the possible role of ACE2 and its end product, angiotensin 1-7 (A1-7), in reducing β cell dedifferentiation during …

4

ACE2 deficiency reduces β-cell mass and impairs β-cell proliferation in obese C57BL/6 mice.

Shoemaker R, Yiannikouris F, Thatcher S, Cassis L. Am J Physiol Endocrinol Metab. 2015 Oct 1;309(7):E621-31. doi: 10.1152/ajpendo.00054.2015. Epub 2015 Aug 4. PMID: 26389599 Free PMC article.

Drugs that inhibit the renin-angiotensin system (RAS) decrease the onset of type 2 diabetes (T2D). Pancreatic islets express RAS components, including angiotensin-converting enzyme 2 (ACE2), which cleaves angiotensin II (Ang II) to angiotensin-(1-7) [Ang-(1-7)]. Overexpression of ACE2 in pancreas of diabetic mice improved glucose homeostasis. The purpose of this study was to determine if deficiency of endogenous ACE2 contributes to islet dysfunction and T2D. We hypothesized that ACE2 deficiency potentiates the decline in β-cell function and augments the development of diet-induced T2D. Male Ace2(+/y) or Ace2(-/y) mice were fed a low-fat (LF) or high-fat (HF) diet for 1 or 4 mo. A subset of 1-mo HF-fed mice were infused with Sal (Sal), losartan (Los), or Ang-(1-7). At 4 mo, while both genotypes of HF-fed mice developed a similar level of insulin resistance, adaptive hyperinsulinemia was reduced in Ace2(-/y) vs. Ace2(+/y) mice. Similarly, in vivo glucose-stimulated insulin secretion (GSIS) was reduced in 1-mo HF-fed Ace2(-/y) compared with Ace2(+/y) mice, resulting in augmented hyperglycemia. The average islet area was significantly smaller in both LF- and HF-fed Ace2(-/y) vs. Ace2(+/y) mice. Additionally, β-cell mass and proliferation were reduced significantly in HF-fed Ace2(-/y) vs. Ace2(+/y) mice. Neither infusion of Los nor Ang-(1-7) was able to correct impaired in vivo GSIS of HF-fed ACE2-deficient mice. These results demonstrate a critical role for endogenous ACE2 in the adaptive β-cell hyperinsulinemic response to HF feeding through regulation of β-cell proliferation and growth. 

5.

Nrf2 Deficiency Upregulates Intrarenal Angiotensin-Converting Enzyme-2 and Angiotensin 1-7 Receptor Expression and Attenuates Hypertension and Nephropathy in Diabetic Mice.

Zhao S, Ghosh A, Lo CS, Chenier I, Scholey JW, Filep JG, Ingelfinger JR, Zhang SL, Chan JSD. Endocrinology. 2018 Feb 1;159(2):836-852. doi: 10.1210/en.2017-00752. PMID: 29211853 Free PMC article.

We investigated the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in renin-angiotensin system (RAS) gene expression in renal proximal tubule cells (RPTCs) and in the development of systemic hypertension and kidney injury in diabetic Akita mice. We used adult male Akita Nrf2 knockout mice and Akita mice treated with trigonelline (an Nrf2 inhibitor) or oltipraz (an Nrf2 activator). We also examined rat immortalized RPTCs (IRPTCs) stably transfected with control plasmids or plasmids containing rat angiotensinogen (Agt), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme-2 (Ace2), or angiotensin 1-7 (Ang 1-7) receptor (MasR) gene promoters. Genetic deletion of Nrf2 or pharmacological inhibition of Nrf2 in Akita mice attenuated hypertension, renal injury, tubulointerstitial fibrosis, and the urinary albumin/creatinine ratio. Furthermore, loss of Nrf2 upregulated RPTC Ace2 and MasR expression, increased urinary Ang 1-7 levels, and downregulated expression of Agt, ACE, and profibrotic genes in Akita mice. In cultured IRPTCs, Nrf2 small interfering RNA transfection or trigonelline treatment prevented high glucose stimulation of Nrf2 nuclear translocation, Agt, and ACE transcription with augmentation of Ace2 and MasR transcription, which was reversed by oltipraz. These data identify a mechanism, Nrf2-mediated stimulation of intrarenal RAS gene expression, by which chronic hyperglycemia induces hypertension and renal injury in diabetes.

Urinary ACE2 in healthy adults and patients with uncomplicated type 1 diabetes.

Cherney DZ, Xiao F, Zimpelmann J, Har RL, Lai V, Scholey JW, Reich HN, Burns KD. Can J Physiol Pharmacol. 2014 Aug;92(8):703-6. doi: 10.1139/cjpp-2014-0065. Epub 2014 May 15. PMID: 24920267

Angiotensin-converting enzyme 2 (ACE2) is expressed in the kidney and may be renoprotective. We determined whether urinary ACE2 enzyme activity and protein levels (ELISA), as well as angiotensinogen and ACE, are elevated during clamped euglycemia (4-6 mmol·L(-1)) in patients with uncomplicated type 1 diabetes (T1D, n = 58) compared with normoglycemic controls (n = 21). We also measured the effect of clamped hyperglycemia (9-11 mmol·L(-1)) on each urinary factor in T1D patients. Urinary ACE2 activity and protein levels were higher during clamped euglycemia in T1D compared with the controls (p < 0.0001). In contrast, urinary angiotensinogen (AGT) levels (p = 0.27) and ACE excretion (p = 0.68) did not differ. In response to clamped hyperglycemia in T1D, urinary ACE2 protein decreased (p < 0.0001), whereas urinary ACE2 activity as well as angiotensinogen and ACE levels remained unchanged. Urinary ACE2 activity and protein expression are increased in T1D patients prior to the onset of clinical complications. Further work is required to determine the functional role of urinary ACE2 in early T1D.

Keywords: ECA2 urinaire; diabetes mellitus; diabète sucré; urinary ACE2. 
7.

Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice.

Salem ES, Grobe N, Elased KM. Am J Physiol Renal Physiol. 2014 Mar 15;306(6):F629-39. doi: 10.1152/ajprenal.00516.2013. Epub 2014 Jan 22. PMID: 24452639 Free PMC article.

Abstract

Angiotensin-converting enzyme 2 (ACE2) is located in several tissues and is highly expressed in renal proximal tubules, where it degrades the vasoconstrictor angiotensin II (ANG II) to ANG-(1-7). Accumulating evidence supports protective roles of ACE2 in several disease states, including diabetic nephropathy. A disintegrin and metalloprotease (ADAM) 17 is involved in the shedding of several transmembrane proteins, including ACE2. Our previous studies showed increased renal ACE2, ADAM17 expression, and urinary ACE2 in type 2 diabetic mice (Chodavarapu H, Grobe N, Somineni HK, Salem ES, Madhu M, Elased KM. PLoS One 8: e62833, 2013). The aim of the present study was to determine the effect of insulin on ACE2 shedding and ADAM17 in type 1 diabetic Akita mice. Results demonstrate increased renal ACE2 and ADAM17 expression and increased urinary ACE2 fragments (≈70 kDa) and albumin excretion in diabetic Akita mice. Immunostaining revealed colocalization of ACE2 with ADAM17 in renal tubules. Renal proximal tubular cells treated with ADAM17 inhibitor showed reduced ACE2 shedding into the media, confirming ADAM17-mediated shedding of ACE2. Treatment of Akita mice with insulin implants for 20 wk normalized hyperglycemia and decreased urinary ACE2 and albumin excretion. Insulin also normalized renal ACE2 and ADAM17 but had no effect on tissue inhibitor of metalloproteinase 3 (TIMP3) protein expression. There was a positive linear correlation between urinary ACE2 and albuminuria, blood glucose, plasma creatinine, glucagon, and triglycerides. This is the first report showing an association between hyperglycemia, cardiovascular risk factors, and increased shedding of urinary ACE2 in diabetic Akita mice. Urinary ACE2 could be used as a biomarker for diabetic nephropathy and as an index of intrarenal ACE2 status.
8. 

High urinary ACE2 concentrations are associated with severity of glucose intolerance and microalbuminuria.

Park SE, Kim WJ, Park SW, Park JW, Lee N, Park CY, Youn BS. Eur J Endocrinol. 2013 Jan 17;168(2):203-10. doi: 10.1530/EJE-12-0782. Print 2013 Feb. PMID: 23144053

OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2) plays an important role in glucose metabolism and renal function. However, the relationship between ACE2 and hyperglycemia or microalbuminuria has not been established in humans. We investigated whether urinar …

9.

Daily exercise training protects against albuminuria and angiotensin converting enzyme 2 shedding in db/db diabetic mice.

Somineni HK, Boivin GP, Elased KM. J Endocrinol. 2014 Apr 22;221(2):235-51. doi: 10.1530/JOE-13-0532. Print 2014 May. PMID: 24756098 Free PMC article.Angiotensin II (Ang II) is involved in induction and progression of renal damage in diabetes. Angiotensin converting enzyme 2 (ACE2) is highly expressed in the kidney and has been shown to be renoprotective by degrading Ang II to Ang-(1-7). A disintegrin and metalloproteinase 17 (ADAM17)-mediated shedding of renal ACE2 contribute to diabetic nephropathy pathogenesis. Lifestyle modification and metformin are recommended as initial therapies for most patients with type 2 diabetes. The aim of this study was to investigate whether exercise training and/or metformin improve glucose homeostasis and albuminuria and downregulate renal ADAM17 and ACE2 shedding in db/db mice. Seven-week-old normal and db/db mice were subjected either to a sedentary existence or exercise training with and without metformin (150 mg/kg per day) for 10 weeks. Exercise training significantly lowered blood glucose, urinary albumin and ACE2 excretion in db/db mice. ADAM17 and ACE2 proteins were co-localized in cortical tubules of the kidney, indicating a possible interaction. Metformin treatment was effective in lowering hyperglycemia only during the first 2 weeks of treatment. Increased renal ADAM17 in 17-week-old db/db mice was corrected by physical exercise but not metformin. In addition, exercise training reduced plasma triglycerides and enhanced insulin levels of db/db mice. In conclusion, exercise training alone and in combination with metformin prevented shedding of renal ACE2 by decreasing ADAM17 protein. Urinary ACE2 could serve as a prognostic tool for the progression of kidney damage and its attenuation by exercise may partially contribute to its renal protection.

10

Angiotensin II type 2 receptor and angiotensin-converting enzyme 2 mediate ischemic renal injury in diabetic and non-diabetic rats.

Sharma N, Malek V, Mulay SR, Gaikwad AB. Life Sci. 2019 Oct 15;235:116796. doi: 10.1016/j.lfs.2019.116796. Epub 2019 Aug 27. PMID: 31470003

However, same is still elusive under AKI and hyperglycaemia comorbidity. Hence, the present study delineates the role of angiotensin-II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) in AKI under normal and hyperglycaemia condition. ...Co-a … Conclusion: We demonstrated that pharmacological activation of AT2R and ACE2 protects DM and ND rats from IRI by preventing oxidative stress, inflammation and apoptosis-mediated tubular damage.
Keywords: ACE2 activator; AT2R agonist; Diabetes; Ischemic renal injury; Renin-angiotensin system.

ACE2 funktioineen tutkijoiden fokuksessa

https://pubmed.ncbi.nlm.nih.gov/32413319/

Metaboliset taudit pandemian aikana

. 2020 May 12;14(4):597-600.

doi: 10.1016/j.dsx.2020.05.025. Online ahead of print.

Mechanism of Inflammatory Response in Associated Comorbidities in COVID-19

Thays Maria Costa de Lucena  ¹ , Ariane Fernandes da Silva Santos  ¹ , Brenda Regina de Lima  ¹ , Maria Eduarda de Albuquerque Borborema  ¹ , Jaqueline de Azevêdo Silva  ²

Affiliations

• PMID: 32417709
• PMCID: PMC7215143
• DOI: 10.1016/j.dsx.2020.05.025

Free PMC article

Abstract

Background and aims: The outbreak of the new coronavirus, SARS-CoV-2, causes a respiratory disease and individuals with pre-existing cardiometabolic disorders display worse prognosis through the infection course. The aim of this minireview is to present epidemiological data related to metabolic comorbidities in association with the SARS-CoV-2.
Methods: This is a narrative mini-review with Pubmed search until April 23, 2020 using the keywords COVID-19, SARS-CoV-2, treatment of coronavirus and following terms: diabetes mellitus, obesity, arterial hypertension, ACE-inhibitors, cytokine storm, immune response and vitamin D.
Results: Studies indicate that obese individuals are more likely to develop infections, and that adipose tissue serves as a pathogen reservoir. In diabetic individuals higher rate of inflammatory processes is seen due to constant glucose recognition by C type lectin receptors. Hypertensive individuals, usually grouped with other conditions, are treated with drugs to reduce blood pressure mostly through ACEi and ARB, that leads to increased ACE2 expression, used by SARS-CoV-2 for human's cell entry. Until now, the studies have shown that individuals with those conditions and affected by COVID-19 present an uncontrolled release of pro-inflammatory cytokines and an unbalanced immune response, leading to the cytokine storm phenomenon. Vitamin D is highlighted as a potential therapeutic target, because in addition to acting on the immune system, it plays an important role in the control of cardiometabolic diseases.
Conclusion: Currently, since there is no proven and effective antiviral therapy for SARS-CoV-2, the efforts should focus on controlling inflammatory response and reduce the risks of associated complications.

Keywords: Diabetes mellitus; Hypertension arterial; Immune response; Obesity; Vitamin D.

Copyright © 2020 Diabetes India. Published by Elsevier Ltd. All rights reserved.

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COP1, RFWD2 E3 ubikitiiniligaasi ja insuliinin eritys

https://www.ncbi.nlm.nih.gov/pubmed/26627735

Cell. 2015 Dec 3;163(6):1457-67. doi: 10.1016/j.cell.2015.10.076. Epub 2015 Nov 25.

β-Cell Insulin Secretion Requires the Ubiquitin Ligase COP1.

Suriben R¹, Kaihara KA², Paolino M¹, Reichelt M³, Kummerfeld SK⁴, Modrusan Z⁵, Dugger DL¹, Newton K¹, Sagolla M³, Webster JD³, Liu J⁴, Hebrok M², Dixit VM⁶.

Author information

Abstract

A variety of signals finely tune insulin secretion by pancreatic β cells to prevent both hyper-and hypoglycemic states. Here, we show that post-translational regulation of the transcription factors ETV1, ETV4, and ETV5 by the ubiquitin ligase COP1 (also called RFWD2) in β cells is critical for insulin secretion. Mice lacking COP1 in β cells developed diabetes due to insulin granule docking defects that were fully rescued by genetic deletion of Etv1, Etv4, and Etv5. Genes regulated by ETV1, ETV4, or ETV5 in the absence of mouse COP1 were enriched in human diabetes-associated genes, suggesting that they also influence human β-cell pathophysiology. In normal β cells, ETV4 was stabilized upon membrane depolarization and limited insulin secretion under hyperglycemic conditions. Collectively, our data reveal that ETVs negatively regulate insulin secretion for the maintenance of normoglycemia.

Copyright © 2015 Elsevier Inc. All rights reserved.

Comment in

• Metabolism: Keeping insulin secretion in check. [Nat Rev Mol Cell Biol. 2016]

PMID:

26627735

DOI:

10.1016/j.cell.2015.10.076

[Indexed for MEDLINE]

Free full text

• 
  

2'O-ribose methylation

https://www.sciencedirect.com/science/article/pii/S1874939918300804

Highlights

•

Ribose 2’-O-methylation is very common RNA modification omnipresent in cellular RNAs (rRNAs/tRNAs/mRNAs/sn(sno)RNAs/miRNAs…).

•

Formation of 2’-O-methylated residues is insured by both protein stand-alone enzymes and by C/D-box sno(s)RNP complexes.

•

Ribose methylation in RNA is dynamic and responds to physiological state of the cell.

•

Ribose methylation is important for regulation of RNA stability, mRNA splicing and translation, as well as innate immune response.

Description

https://www.ebi.ac.uk/interpro/entry/InterPro/IPR013123/

Most cellular RNAs undergo a number of post-transcriptional nucleoside modifications. While the biological role of many of these modifications is unknown, some have been shown to be necessary for cell growth or for resistance to antibiotics

^{[1, 2]}

. One of the most common modifications is 2'O-ribose methylation catalysed by the RNA 2'O-ribose methyltransferases, a large enzyme family that transfer a methyl group from S-adenosyl-L-methionine (AdoMet) to the 2'-OH group of the backbone ribose

^[3]

.

This entry represents a substrate-binding domain found in a variety of bacterial and mitochondrial RNA 2'-O ribose methyltransferases. These include the bacterial enzyme RlmB, which specifically methylates the conserved nucleotide guanosine 2251 in 23S RNA, and PET56, which specifically methylates the equivalent guanosine in mitochondrial 21S RNA

^{[4, 1]}

. This domain forms a four-stranded mixed beta sheet similar to that found in other RNA binding enzymes

^[5]

. It shows considerable conformational flexibility which is thought to be important for its ability to bind RNA.

Wikipedia

2'-O-methylation

From Wikipedia, the free encyclopedia

Jump to navigation Jump to search

2'-O-methyl-adenosine, a modified adenosine.

2'-O-methylation is a common nucleoside modification of RNA, where a methyl group is added to the 2' hydroxyl of the ribose moiety of a nucleoside, producing a methoxy group. 2'-O-methylated nucleosides are mostly found in ribosomal RNA and small nuclear RNA and occur in the functionally essential regions of the ribosome and spliceosome.^[1] Currently, about 1210 2'-O-methylations (2'-O-Me) have been identified in mammals and yeast and deposited in RMBase (RNA Modification Base) database.^[2]
Having the chemical properties intermediate between RNA and DNA, 2'-O-methylation is presumed to have one of the reactive group of RNA molecules on early earth that would have given rise to DNA.^[3]
Recently a novel method to map 2'-O ribose methylations by high throughput sequencing has been published.^[4] The method is quantitative and maps all modifications in a single experiment.

RIBOOSI , cADPr

cADPr, syklinen ADPriboosi

• Review
• Published: 31 January 2000

Cyclic ADP-ribose

• Andreas H. Guse 

Journal of Molecular Medicine volume 78, pages26–35(2000) Cite this article

Abstract.

The Ca²⁺-mobilizing natural compound cyclic ADP-ribose was discovered in sea urchin egg homogenates. Recently the involvement of cyclic ADP-ribose in Ca²⁺ signaling has been demonstrated in diverse biological systems spanning protozoa, plants, and cells from invertebrate, mammalian, and human sources. ADP-ribosyl cyclases synthesize cyclic ADP-ribose. Several candidate proteins for these enzymes have been proposed, including membrane-bound NAD⁺ glycohydrolases such as CD38 and soluble enzyme activities from various tissues and cells. Ca²⁺ mobilization by cyclic ADP-ribose is believed to proceed via the ryanodine receptor/Ca²⁺ channel, probably via binding proteins for cyclic ADP-ribose. Several antagonistic derivatives of cyclic ADP-ribose have been synthesized, some of which have been successfully used to demonstrate the involvement of cyclic ADP-ribose in sea urchin egg fertilization, glucose-dependent insulin secretion in pancreatic β-cells, and activation and proliferation of human T-lymphocytes.

• 
  

UDP-Gal ja laktaatio

https://www.ncbi.nlm.nih.gov/pubmed/?term=UDP-galactose+%2C+lactation

Search results

Items: 6

Select item 226490651.

Gene regulation of UDP-galactose synthesis and transport: potential rate-limiting processes in initiation of milk production in humans.

Mohammad MA, Hadsell DL, Haymond MW.

Am J Physiol Endocrinol Metab. 2012 Aug 1;303(3):E365-76. doi: 10.1152/ajpendo.00175.2012. Epub 2012 May 29.

PMID:

22649065

Free PMC Article

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Select item 79654582.

Metabolites of lactose synthesis in milk from diabetic and nondiabetic women during lactogenesis II.

Arthur PG, Kent JC, Hartmann PE.

J Pediatr Gastroenterol Nutr. 1994 Jul;19(1):100-8.

PMID:

7965458

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Select item 17915013.

Metabolites of lactose synthesis in milk from women during established lactation.

Arthur PG, Kent JC, Hartmann PE.

J Pediatr Gastroenterol Nutr. 1991 Oct;13(3):260-6.

PMID:

1791501

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Select item 18614544.

Galactose increase in an infant whose mother is heterozygous for peripheral uridine diphosphate galactose-4-epimerase deficiency.

Keller KM, Wirth S, Sewell AC, Shin YS.

J Inherit Metab Dis. 1991;14(1):114-5. No abstract available.

PMID:

1861454

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Select item 27387865.

Milk produced by mothers with galactosemia.

Ng WG, Xu YK, Kaufman F, Donnell GN.

J Pediatr. 1989 Jul;115(1):166-7. No abstract available.

PMID:

2738786

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Select item 61787666.

Acid-soluble nucleotides of human milk at different stages of lactation.

Gil A, Sanchez-Medina F.

J Dairy Res. 1982 May;49(2):301-7.

PMID:

6178766

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Hyvää Uutta Vuotta 2020. Mielessäni on tärkeä molekyyli UDP-gal.

UDP-Gal
PubMed haku 2.1. 2020.
https://www.ncbi.nlm.nih.gov/pubmed/?term=UDP-galactose

Best matches for UDP-galactose:

Cryptococcus neoformans UGT1 encodes a UDP-Galactose/UDP-GalNAc transporter. Li LX et al. Glycobiology. (2017)

One-Pot Synthesis of Hyperoside by a Three-Enzyme Cascade Using a UDP-Galactose Regeneration System. Pei J et al. J Agric Food Chem. (2017)

UDP-Glucose 4-Epimerase and β-1,4-Galactosyltransferase from the Oyster Magallana gigas as Valuable Biocatalysts for the Production of Galactosylated Products. Song HB et al. Int J Mol Sci. (2018)

 Hakulöytöjä muuten seuraavat_

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• Poimin muutaman, jotka merkitsevät ihmisen (Homo sapiens)  kannalta olennaista: 

HAKU:  "UDP-galactose, Homo sapiens "
Löytöjä: 
 https://www.ncbi.nlm.nih.gov/pubmed/?term=UDP-galactose++homo+sapiens

Best matches for UDP-galactose homo sapiens:

Hereditary galactosemia. Demirbas D et al. Metabolism. (2018)

Cryptococcus neoformans UGT1 encodes a UDP-Galactose/UDP-GalNAc transporter. Li LX et al. Glycobiology. (2017)

Inherited thrombocytopenia associated with mutation of UDP-galactose-4-epimerase (GALE). Seo A et al. Hum Mol Genet. (2019).

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• Artikkeleita  kahden viime vuoden ajalta: 

The synonymous 903C>G mutation in the alpha 1,4-galactosyltransferase gene in a Chinese woman with habitual abortion: A case report.

Lv X, Chen Y, Luo Y, Li L, Wang H.

Medicine (Baltimore). 2019 Aug;98(31):e16361. doi: 10.1097/MD.0000000000016361.

OUTCOMES:The patient was the rare p phenotype in P1P blood system and the patient's habitual abortion was caused by anti-PP1P antibody which was generated naturally in persons with p phenotype. There was a mutation (903C>G, CCC>CCG) in the 3rd exon of A4GALT gene, which is likely a significant contributor to p phenotype.LESSONS: This is the first case of habitual abortion caused by p phenotype due to independent 903C>G homozygous mutation with no similar record reported before, which indicates that it is a new class of mutation that leads to p phenotype.

Free PMC Article  ( Asetan linkin Veri ja hyytyminen- blogiini 2.1. 2020 veriryhmätietojen joukkoon)

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Select item 312408952.

First Case in Korea of a Patient With Anti-PP1Pk Antibodies: Successful Blood Management via Acute Normovolemic Hemodilution (AMH).

Ha C, Choi S, Yu H, Chun S, Kim KH, Lee JH, Han IW, Cho D.

Ann Lab Med. 2019 Nov;39(6):602-605. doi: 10.3343/alm.2019.39.6.602. No abstract available.Free PMC Article

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  ( Asetan linkin Veri ja hyytyminen- blogiini 2.1. 2020 veriryhmätietojen joukkoon) 
 

Select item 309103753.

Fetal phenotypes of congenital disorder of glycosylation: A case presentation.

Yang YD, Xu LL, Li DZ.

Eur J Obstet Gynecol Reprod Biol. 2019 May;236:257-258. doi: 10.1016/j.ejogrb.2019.03.013. Epub 2019 Mar 19. No abstract available.

Congenital disorders of glycosylation (CDG) are a rapidly growing and genetically and clinically heterogeneous family caused by impaired synthesis of glycoconjugates [1]. Affected individuals have multi-systemic manifestations, mainly profound neurological deficiencies, growth failure, facial dysmorphisms, and a wide range of multiorgan symptoms. Currently, all reported CDG cases are child patients. We here first present a prenatal case of CDG due to a de novo variant in the X-linked gene SLC35A2.

Similar articles

 

Select item 308710234.

Identification of Leishmania major UDP-Sugar Pyrophosphorylase Inhibitors Using Biosensor-Based Small Molecule Fragment Library Screening.

Prakash O, Führing J, Post J, Shepherd SM, Eadsforth TC, Gray D, Fedorov R, Routier FH.

Molecules. 2019 Mar 12;24(5). pii: E996. doi: 10.3390/molecules24050996.

Leishmaniasis is a neglected disease that is caused by different species of the protozoan parasite Leishmania, and it currently affects 12 million people worldwide. The antileishmanial therapeutic arsenal remains very limited in number and efficacy, and there is no vaccine for this parasitic disease. One pathway that has been genetically validated as an antileishmanial drug target is the biosynthesis of uridine diphosphate-glucose (UDP-Glc), and its direct derivative UDP-galactose (UDP-Gal). De novo biosynthesis of these two nucleotide sugars is controlled by the specific UDP-glucose pyrophosphorylase (UGP).

 Leishmania parasites additionally express a UDP-sugar pyrophosphorylase (USP) responsible for monosaccharides salvage that is able to generate both UDP-Gal and UDP-Glc. The inactivation of the two parasite pyrophosphorylases UGP and USP, results in parasite death. 

The present study reports on the identification of structurally diverse scaffolds for the development of USP inhibitors by fragment library screening. Based on this screening, we selected a small set of commercially available compounds, and identified molecules that inhibit both Leishmania major USP and UGP, with a half-maximal inhibitory concentration in the 100 µM range. The inhibitors were predicted to bind at allosteric regulation sites, which were validated by mutagenesis studies. This study sets the stage for the development of potent USP inhibitors.Free PMC Article

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Select item 307180575.

The ability of an LC-MS/MS-based erythrocyte GALT enzyme assay to predict the phenotype in subjects with GALT deficiency.

Demirbas D, Huang X, Daesety V, Feenstra S, Haskovic M, Qi W, Gubbels CS, Hecht L, Levy HL, Waisbren SE, Berry GT.

Mol Genet Metab. 2019 Apr;126(4):368-376. doi: 10.1016/j.ymgme.2019.01.016. Epub 2019 Jan 22.

GALT deficiency is a rare genetic disorder of carbohydrate metabolism. Due to the decreased activity or absence of the enzyme galactose-1-phosphate uridylyltransferase (GALT), cells from affected individuals are unable to metabolize galactose normally. Lactose consumption in the newborn period could potentially lead to a lethal disease process with multi-organ involvement. In contrast to the newborn-stage disease, however, a galactose-restricted diet does not prevent long-term complications such as central nervous system (CNS) dysfunction with speech defects, learning disability and neurological disease in addition to hypergonadotropic hypogonadism or primary ovarian insufficiency (POI) in females. As the literature suggests an association between GALT enzyme activity and the long-term complications, it is of importance to have a highly sensitive assay to quantify the GALT enzyme activity. To that end, we had developed a sensitive and accurate LC-MS/MS method to measure GALT enzyme activity. Its ability to predict outcome is the subject of this report.RESULTS:
The LC-MS/MS method measured GALT activity as low as 0.2%, whereas other methods showed no detectable activity. Largely due to GALT activities that were over 1%, the LC-MS/MS measurements were not significantly different than values obtained in other laboratories using other methodologies. Severe long-term complications were less frequently noted in subjects with >1% activity. Patients with a p.Q188R/p.Q188R genotype have no residual enzyme activity in erythrocytes.CONCLUSION:
Our LC-MS/MS assay may be necessary to accurately quantify residual GALT activities below 5%. The data suggest that patients with >1% residual activity are less likely to develop diet-independent long-term complications. However, much larger sample sizes are needed to properly assess the clinical phenotype in patients with residual enzyme activities between 0.1 and 5%.

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Select item 306419436.

SLC35A5 Protein-A Golgi Complex Member with Putative Nucleotide Sugar Transport Activity.

Sosicka P, Bazan B, Maszczak-Seneczko D, Shauchuk Y, Olczak T, Olczak M.

Int J Mol Sci. 2019 Jan 11;20(2). pii: E276. doi: 10.3390/ijms20020276.

Solute carrier family 35 member A5 (SLC35A5) is a member of the SLC35A protein subfamily comprising nucleotide sugar transporters. However, the function of SLC35A5 is yet to be experimentally determined. In this study, we inactivated the SLC35A5 gene in the HepG2 cell line to study a potential role of this protein in glycosylation. Introduced modification affected neither N- nor O-glycans. There was also no influence of the gene knock-out on glycolipid synthesis. However, inactivation of the SLC35A5 gene caused a slight increase in the level of chondroitin sulfate proteoglycans. Moreover, inactivation of the SLC35A5 gene resulted in the decrease of the uridine diphosphate (UDP)-glucuronic acid, UDP-N-acetylglucosamine, and UDP-N-acetylgalactosamine Golgi uptake, with no influence on the UDP-galactose transport activity. Further studies demonstrated that SLC35A5 localized exclusively to the Golgi apparatus. Careful insight into the protein sequence revealed that the C-terminus of this protein is extremely acidic and contains distinctive motifs, namely DXEE, DXD, and DXXD. Our studies show that the C-terminus is directed toward the cytosol. We also demonstrated that SLC35A5 formed homomers, as well as heteromers with other members of the SLC35A protein subfamily. In conclusion, the SLC35A5 protein might be a Golgi-resident multiprotein complex member engaged in nucleotide sugar transport.Free PMC Article

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Select item 305923007.

A whole genome approach for discovering the genetic basis of blood group antigens: independent confirmation for P1 and Xg^a.

Lane WJ, Aguad M, Smeland-Wagman R, Vege S, Mah HH, Joseph A, Blout CL, Nguyen TT, Lebo MS, Sidhu M, Lomas-Francis C, Kaufman RM, Green RC, Westhoff CM; MedSeq Project.

Transfusion. 2019 Mar;59(3):908-915. doi: 10.1111/trf.15089. Epub 2018 Dec 28.

(Viite veriryhmätekijöiden joukkoon Veri ja hyytyminen blogiini 2.1. 2020)

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Select item 305020908.

Lactosylceramide synthase β-1,4-GalT-V: A novel target for the diagnosis and therapy of human colorectal cancer.

Chatterjee SB, Hou J, Bandaru VVR, Pezhouh MK, Syed Rifat Mannan AA, Sharma R.

Biochem Biophys Res Commun. 2019 Jan 8;508(2):380-386. doi: 10.1016/j.bbrc.2018.11.149. Epub 2018 Nov 28.

PMID:

30502090

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Select item 304712829.

Immunoregulatory Siglec ligands are abundant in human and mouse aorta and are up-regulated by high glucose.

Zhang Y, Zheng Y, Li J, Nie L, Hu Y, Wang F, Liu H, Fernandes SM, Zhong Q, Li X, Schnaar RL, Jia Y.

Life Sci. 2019 Jan 1;216:189-199. doi: 10.1016/j.lfs.2018.11.049. Epub 2018 Nov 22.

PMID:

30471282

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Select item 3035621310.

Palladium-mediated enzyme activation suggests multiphase initiation of glycogenesis.

Bilyard MK, Bailey HJ, Raich L, Gafitescu MA, Machida T, Iglésias-Fernández J, Lee SS, Spicer CD, Rovira C, Yue WW, Davis BG.

Nature. 2018 Nov;563(7730):235-240. doi: 10.1038/s41586-018-0644-7. Epub 2018 Oct 24.

PMID:

30356213

Free Article

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Select item 3029843911.

The use of PBPK modeling across the pediatric age range using propofol as a case.

Michelet R, Van Bocxlaer J, Allegaert K, Vermeulen A.

J Pharmacokinet Pharmacodyn. 2018 Dec;45(6):765-785. doi: 10.1007/s10928-018-9607-8. Epub 2018 Oct 8.

PMID:

30298439

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Select item 3024763612.

Inherited thrombocytopenia associated with mutation of UDP-galactose-4-epimerase (GALE).

Seo A, Gulsuner S, Pierce S, Ben-Harosh M, Shalev H, Walsh T, Krasnov T, Dgany O, Doulatov S, Tamary H, Shimamura A, King MC.

Hum Mol Genet. 2019 Jan 1;28(1):133-142. doi: 10.1093/hmg/ddy334.

Severe thrombocytopenia, characterized by dysplastic megakaryocytes and intracranial bleeding, was diagnosed in six individuals from a consanguineous kindred. Three of the individuals were successfully treated by bone marrow transplant. Whole-exome sequencing and homozygosity mapping of multiple family members, coupled with whole-genome sequencing to reveal shared non-coding variants, revealed one potentially functional variant segregating with thrombocytopenia under a recessive model: GALE p.R51W (c.C151T, NM_001127621). The mutation is extremely rare (allele frequency = 2.5 × 10-05), and the likelihood of the observed co-segregation occurring by chance is 1.2 × 10-06. GALE encodes UDP-galactose-4-epimerase, an enzyme of galactose metabolism and glycosylation responsible for two reversible reactions: interconversion of UDP-galactose with UDP-glucose and interconversion of UDP-N-acetylgalactosamine with UDP-N-acetylglucosamine. The mutation alters an amino acid residue that is conserved from yeast to humans. The variant protein has both significantly lower enzymatic activity for both interconversion reactions and highly significant thermal instability. Proper glycosylation is critical to normal hematopoiesis, in particular to megakaryocyte and platelet development, as reflected in the presence of thrombocytopenia in the context of congenital disorders of glycosylation. Mutations in GALE have not previously been associated with thrombocytopenia. Our results suggest that GALE p.R51W is inadequate for normal glycosylation and thereby may impair megakaryocyte and platelet development. If other mutations in GALE are shown to have similar consequences, this gene may be proven to play a critical role in hematopoiesis.Free PMC Article

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Select item 3021977313.

The relevance of ceramides and their synthesizing enzymes for multiple sclerosis.

Kurz J, Brunkhorst R, Foerch C, Blum L, Henke M, Gabriel L, Ulshöfer T, Ferreirós N, Parnham MJ, Geisslinger G, Schiffmann S.

Clin Sci (Lond). 2018 Aug 17;132(17):1963-1976. doi: 10.1042/CS20180506. Print 2018 Sep 14.

Ceramide synthases (CerS) synthesize chain length specific ceramides (Cer), which mediate cellular processes in a chain length-dependent manner. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed that the genetic deletion of CerS2 suppresses EAE pathology by interaction with granulocyte-colony stimulating factor (G-CSF) signaling and CXC motif chemokine receptor 2 (CXCR2) expression, leading to impaired neutrophil migration. In the present study, we investigated the importance of Cers and their synthesizing/metabolizing enzymes in MS. For this purpose, a longitudinal study with 72 MS patients and 25 healthy volunteers was performed. Blood samples were collected from healthy controls and MS patients over 1- or 3-year periods, respectively. Immune cells were counted using flow cytometry, ceramide levels were determined using liquid chromatography-tandem mass spectrometry, and mRNA expression was analyzed using quantitative PCR. 

In white blood cells, C16-LacCer and C24-Cer were down-regulated in MS patients in comparison with healthy controls.

 In plasma, C16-Cer, C24:1-Cer, C16-GluCer, and C24:1-GluCer were up-regulated and 

C16-LacCer was down-regulated in MS patients in comparison with healthy controls. 

Blood samples from MS patients were characterized by an increased B-cell number. However, there was no correlation between B-cell number and Cer levels. mRNA expression of Cer metabolizing enzymes and G-CSF signaling enzymes was significantly increased in MS patients.

 Interestingly, G-CSF receptor (G-CSFR) and CXCR2 mRNA expression correlated with CerS2 and UDP-glucose Cer glucosyltransferase (UGCG) mRNA expression. 

In conclusion, our results indicate that Cer metabolism is linked to G-CSF signaling in MS.

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Select item 3019403814.

SLC35A2-related congenital disorder of glycosylation: Defining the phenotype.

Yates TM, Suri M, Desurkar A, Lesca G, Wallgren-Pettersson C, Hammer TB, Raghavan A, Poulat AL, Møller RS, Thuresson AC, Balasubramanian M.

Eur J Paediatr Neurol. 2018 Nov;22(6):1095-1102. doi: 10.1016/j.ejpn.2018.08.002. Epub 2018 Aug 27.

PMID:

30194038

Free Article

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Select item 3017578215.

Acquired Resistance to Shiga Toxin-Induced Apoptosis by Loss of CD77 Expression in Human Myelogenous Leukemia Cell Line, THP-1.

Hattori T, Watanabe-Takahashi M, Nishikawa K, Naito M.

Biol Pharm Bull. 2018;41(9):1475-1479. doi: 10.1248/bpb.b18-00277.

PMID:

30175782

Free Article

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Select item 3015448016.

AXER is an ATP/ADP exchanger in the membrane of the endoplasmic reticulum.

Klein MC, Zimmermann K, Schorr S, Landini M, Klemens PAW, Altensell J, Jung M, Krause E, Nguyen D, Helms V, Rettig J, Fecher-Trost C, Cavalié A, Hoth M, Bogeski I, Neuhaus HE, Zimmermann R, Lang S, Haferkamp I.

Nat Commun. 2018 Aug 28;9(1):3489. doi: 10.1038/s41467-018-06003-9.

To fulfill its role in protein biogenesis, the endoplasmic reticulum (ER) depends on the Hsp70-type molecular chaperone BiP, which requires a constant ATP supply. However, the carrier that catalyzes ATP uptake into the ER was unknown. Here, we report that our screen of gene expression datasets for member(s) of the family of solute carriers that are co-expressed with BiP and are ER membrane proteins identifies SLC35B1 as a potential candidate. Heterologous expression of SLC35B1 in E. coli reveals that SLC35B1 is highly specific for ATP and ADP and acts in antiport mode. Moreover, depletion of SLC35B1 from HeLa cells reduces ER ATP levels and, as a consequence, BiP activity. Thus, human SLC35B1 may provide ATP to the ER and was named AXER (ATP/ADP exchanger in the ER membrane). Furthermore, we propose an ER to cytosol low energy response regulatory axis (termed lowER) that appears as central for maintaining ER ATP supply.Free PMC Article

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Select item 3014302617.

Profiling of intracellular metabolites produced from galactose and its potential for galactosemia research.

van Weeghel M, Welling L, Treacy EP, Wanders RJA, Ferdinandusse S, Bosch AM.

Orphanet J Rare Dis. 2018 Aug 24;13(1):146. doi: 10.1186/s13023-018-0888-1.

Schematic overview of galactose metabolism: Galactose [1] is converted by galactokinase (GALK1) to galactose-1-phosphate (Gal-1-P) [2] which is subsequently converted to uridine diphosphate (UDP)-galactose [3] by galactose-1-phosphate uridyltransferase (GALT). For this last conversion UDP-glucose [4] is used as a donor for the UDP and as a receptor for the phosphate to produce UDP-galactose [3] and glucose-1-phosphate [5]. Produced glucose-1-phosphate [5] can enter glycolysis via phosphoglucomutase to glucose-6-phosphate and subsequently enter the tricarboxylic acid (TCA) cycle. UDP-galactose [3] can be converted by UDP-galactose-4-epimerase (GALE) to UDP-glucose [4]. The numbered carbons are used in the galactose metabolites profiling (GMP) measurementsFree PMC Article

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Select item 2990709218.

Mosaicism of the UDP-Galactose transporter SLC35A2 in a female causing a congenital disorder of glycosylation: a case report.

Westenfield K, Sarafoglou K, Speltz LC, Pierpont EI, Steyermark J, Nascene D, Bower M, Pierpont ME.

BMC Med Genet. 2018 Jun 15;19(1):100. doi: 10.1186/s12881-018-0617-6.

PMID:

29907092

Free PMC Article

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Select item 2975762419.

Steric Control of the Rate-Limiting Step of UDP-Galactopyranose Mutase.

Pierdominici-Sottile G, Cossio-Pérez R, Da Fonseca I, Kizjakina K, Tanner JJ, Sobrado P.

Biochemistry. 2018 Jul 3;57(26):3713-3721. doi: 10.1021/acs.biochem.8b00323. Epub 2018 May 18.

PMID:

29757624

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Single nucleotide polymorphisms in A4GALT spur extra products of the human Gb3/CD77 synthase and underlie the P1PK blood group system.

Kaczmarek R, Szymczak-Kulus K, Bereźnicka A, Mikołajczyk K, Duk M, Majorczyk E, Krop-Watorek A, Klausa E, Skowrońska J, Michalewska B, Brojer E, Czerwinski M.

PLoS One. 2018 Apr 30;13(4):e0196627. doi: 10.1371/journal.pone.0196627. eCollection 2018.

Contrary to the mainstream blood group systems, P1PK continues to puzzle and generate controversies over its molecular background. The P1PK system comprises three glycosphingolipid antigens: Pk, P1 and NOR, all synthesised by a glycosyltransferase called Gb3/CD77 synthase. The Pk antigen is present in most individuals, whereas P1 frequency is lesser and varies regionally, thus underlying two common phenotypes: P1, if the P1 antigen is present, and P2, when P1 is absent. Null and NOR phenotypes are extremely rare. 

To date, several single nucleotide polymorphisms (SNPs) have been proposed to predict the P1/P2 status, but it has not been clear how important they are in general and in relation to each other, nor has it been clear how synthesis of NOR affects the P1 phenotype. Here, we quantitatively analysed the phenotypes and A4GALT transcription in relation to the previously proposed SNPs in a sample of 109 individuals, and addressed potential P1 antigen level confounders, most notably the red cell membrane cholesterol content. While all the SNPs were associated with the P1/P2 blood type and rs5751348 was the most reliable, we found large differences in P1 level within groups defined by their genotype and substantial intercohort overlaps, which shows that the P1PK blood group system still eludes full understanding.Free PMC Article

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