Metabolic Response to Iron Deficiency in Saccharomyces cerevisiae

Shakoury‐Elizeh, Minoo; Protchenko, Olga; Berger, Alvin; Cox, James E.; Gable, Kenneth; Dunn, Teresa M.; Prinz, William A.; Bard, Martin; Philpott, Caroline C.

doi:10.1074/jbc.m109.091710

Cited by 163 publications

(200 citation statements)

References 49 publications

(60 reference statements)

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“…Moreover, seven up-regulated genes were associated with the pyruvate metabolic process. Interestingly, pyruvate production and increased glycolysis has also been observed during iron deprivation in S. cerevisiae (68). Our microarray data also revealed several transcriptional regulator genes that showed Cap2 dependence, of which 25 genes were up-regulated, and 15 were down-regulated.…”

Section: Albicans Cap2 Is a Hap4l-bzip Bipartite Domain Protein-mentioning

confidence: 62%

Cap2-HAP Complex Is a Critical Transcriptional Regulator That Has Dual but Contrasting Roles in Regulation of Iron Homeostasis in Candida albicans

Singh¹,

Prasad²,

Sinha³

et al. 2011

Journal of Biological Chemistry

211

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Iron homeostasis is highly regulated in organisms across evolutionary time scale as iron is essential for various cellular processes. In a computational screen, we identified the Yap/bZIP domain family in Candida clade genomes. Cap2/Hap43 is essential for C. albicans growth under iron-deprivation conditions and for virulence in mouse. Cap2 has an amino-terminal bipartite domain comprising a fungal-specific Hap4-like domain and a bZIP domain. Our mutational analyses showed that both the bZIP and Hap4-like domains perform critical and independent functions for growth under iron-deprivation conditions. Transcriptome analysis conducted under iron-deprivation conditions identified about 16% of the C. albicans ORFs that were differentially regulated in a Cap2-dependent manner. Microarray data also suggested that Cap2 is required to mobilize iron through multiple mechanisms; chiefly by activation of genes in three iron uptake pathways and repression of iron utilizing and iron storage genes. The expression of HAP2, HAP32, and HAP5, core components of the HAP regulatory complex was induced in a Cap2-dependent manner indicating a feed-forward loop. In a feed-back loop, Cap2 repressed the expression of Sfu1, a negative regulator of iron uptake genes. Cap2 was coimmunoprecipitated with Hap5 from cell extracts prepared from iron-deprivation conditions indicating an in vivo association. ChIP assays demonstrated Hap32-dependent recruitment of Hap5 to the promoters of FRP1 (Cap2-induced) and ACO1 (Cap2-repressed). Together our data indicates that the Cap2-HAP complex functions both as a positive and a negative regulator to maintain iron homeostasis in C. albicans.

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Section: Albicans Cap2 Is a Hap4l-bzip Bipartite Domain Protein-mentioning

confidence: 62%

Cap2-HAP Complex Is a Critical Transcriptional Regulator That Has Dual but Contrasting Roles in Regulation of Iron Homeostasis in Candida albicans

Singh¹,

Prasad²,

Sinha³

et al. 2011

Journal of Biological Chemistry

211

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“…We made significant attempts to increase the iron content within the enzyme, including reduction of the zinc content in the expression media, stripping out zinc with subsequent addition of iron during purification, and manipulation of the yeast expression conditions to favor iron incorporation over zinc (42). Although these attempts led to the production of highly purified enzyme with iron incorporated at the dimetal center up to ϳ50%, we were unsuccessful at achieving 100% replacement with iron.…”

Section: Discussionmentioning

confidence: 99%

The Crystal Structure of an Integral Membrane Fatty Acid α-Hydroxylase

Zhu

Koszelak-Rosenblum

Connelly

et al. 2015

Journal of Biological Chemistry

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Neuronal electrical impulse propagation is facilitated by the myelin sheath, a compact membrane surrounding the axon. The myelin sheath is highly enriched in galactosylceramide (GalCer) and its sulfated derivative sulfatide. Over 50% of GalCer and sulfatide in myelin is hydroxylated by the integral membrane enzyme fatty acid 2-hydroxylase (FA2H). GalCer hydroxylation contributes to the compact nature of the myelin membrane, and mutations in FA2H result in debilitating leukodystrophies and spastic paraparesis. We report here the 2.6 Å crystal structure of sphingolipid ␣-hydroxylase (Scs7p), a yeast homolog of FA2H. The Scs7p core is composed of a helical catalytic cap domain that sits atop four transmembrane helices that anchor the enzyme in the endoplasmic reticulum. The structure contains two zinc atoms coordinated by the side chains of 10 highly conserved histidines within a dimetal center located near the plane of the cytosolic membrane. We used a yeast genetic approach to confirm the important role of the dimetal-binding histidines in catalysis and identified Tyr-322 and Asp-323 as critical determinants involved in the hydroxylase reaction. Examination of the Scs7p structure, coupled with molecular dynamics simulations, allowed for the generation of a model of ceramide binding to Scs7p. Comparison of the Scs7p structure and substratebinding model to the structure of steroyl-CoA desaturase revealed significant differences in the architecture of the catalytic cap domain and location of the dimetal centers with respect to the membrane. These observations provide insight into the different mechanisms of substrate binding and recognition of substrates by the hydroxylase and desaturase enzymes.

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“…Also, Ford et al (34) found in a cross-sectional study of 8296 adults who participated in the National Health and Nutrition Examination Survey (NHANES) that iron deficiency tends to increase HbA1c level rather than decreasing it. In addition, Shakoury-Elizeh et al (35) showed that iron deficiency leads to impairment in glucose metabolism by altering glucose storage.…”

Section: Discussionmentioning

confidence: 99%

Body iron stores and the risk of type 2 diabetes in middle-aged men

Aregbesola

Voutilainen

Virtanen

et al. 2013

European Journal of Endocrinology

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Objective: We investigated the risk of type 2 diabetes mellitus (T2DM) over a wide range of body iron stores. Methods: Prospective cohort of 1613 men in the Kuopio Ischemic Heart Disease Risk Factor study, aged 42-60 years, free of T2DM and hereditary hemochromatosis at baseline in [1984][1985][1986][1987][1988][1989]. Baseline serum ferritin (sF) and serum-soluble transferrin receptor (sTfR) concentrations were used to predict incident T2DM. T2DM was assessed by questionnaires, blood glucose measurements, and medication reimbursement register. Results: There were 331 cases of incident T2DM during the mean follow-up of 16.8 years (27 098 person-years). At baseline, subjects who later developed T2DM had average sF concentrations of 191 mg/l (S.D. 155) vs 151 mg/l (S.D. 119) among those who remained healthy, P!0.001. In a multivariate-adjusted logistic regression, each 100 mg/l increase in sF corresponded to an average of 14% increased (odds ratioZ1.14, 95% CI 1.03-1.26, PZ0.009) risk of developing T2DM. In a Cox regression, a markedly increased risk of developing T2DM was observed from the fourth sF quintile (185 mg/l, the median) upward (hazard ratio (HR) first vs fifth quintileZ1.5, 95% CI 1.0-2.2, P-trendZ0.05). In a corresponding Cox model in sTfR, the subjects in the third quintile (1840 mg/l, the median) had the least risk (HRZ0.63, 95% CI 0.42-0.97, PZ0.04). Conclusions: Body iron within the sF reference range is not an important determinant of T2DM risk, whereas high normal and above is associated with markedly increased risk. Iron depletion toward iron deficiency as assessed by sTfR is not protective against T2DM. A rule of thumb safe range could be 30-200 mg/l of sF.

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Metabolic Response to Iron Deficiency in Saccharomyces cerevisiae

Cited by 163 publications

References 49 publications

Cap2-HAP Complex Is a Critical Transcriptional Regulator That Has Dual but Contrasting Roles in Regulation of Iron Homeostasis in Candida albicans

Cap2-HAP Complex Is a Critical Transcriptional Regulator That Has Dual but Contrasting Roles in Regulation of Iron Homeostasis in Candida albicans

The Crystal Structure of an Integral Membrane Fatty Acid α-Hydroxylase

Body iron stores and the risk of type 2 diabetes in middle-aged men

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