Nutrigenomics

1. Health, Nutrition, DNA2. History Biochemical Pathways, Vitamins and Omics3. Triage Theory4. Structural Proteins/DNA variations5. Conclusions

David R. Bachinsky, Ph.D., M.S.

Cellanyx Diagnostics 5 June 2013

Genotypes and Nutrition ≠ simple Phenotypes

“The main distinguishing characteristic between man and the lower animals is the desire to take pills.” Mark Twain

Nutrigenomics: goals and strategies. Michael Müller & Sander Kersten http://www.nature.com/nrg/journal/v4/n4/full/nrg1047.html http://nutrigene.4t.com/

Nutrigenomics is a branch of nutritional genomics and is the study of the effects of foods and food constituents on gene expression.

Nutritional genomics is a science studying the relationship between human genome, nutrition and health

Michael Muller

Overweight and Obesity (CD) http://www.cdc.gov/obesity/data/adult.html

Obesity is common, serious and costly. More than one-third of U.S. adults (35.7%) are obese. The medical costs for people who are obese were $1,429 higher than those of normal weight. Obesity affects some groups more than others. Non-Hispanic blacks have the highest age-adjusted rates of obesity (49.5%) compared with Mexican Americans (40.4%), all Hispanics (39.1%) and non-Hispanic whites (34.3%).

Epigenetic Biomarkers May Predict If a Specific Diet and Exercise Regimen Will Work. 29 May 2013 . New research in The FASEB Journal describes five epigenetic biomarkers associated with better weight loss response in Spanish adolescents participating in the 10-week EVASYON weight loss program. After validation, 5 regions located in or near AQP9, DUSP22, HIPK3, TNNT1, and TNNI3 genes showed differential methylation levels between high and low responders to the multidisciplinary weight loss intervention. http://www.fasebj.org/content/27/6/2504

“Genotype Patterns Predict Weight Loss Success: The Right Diet Does Matter” INTERLEUKIN GENETICS, INC. AND STANFORD UNIVERSITY REPORT GENETIC TEST IMPROVES WEIGHT LOSS SUCCESS AHA Meeting. March 3, 2010. Individuals on genotype-appropriate diets lost 5.3 percent of body weight compared to individuals on diets not matched to their genotype, who experienced only 2.3 percent weight loss. FABP2: Ala54Thr, PPARG:Pro12Ala, ADRB2: Arg16Gly, Gln27Glu and ADRB3: Arg64Trp

http://scienceblogs.com/pharyngula/2008/07/22/epigenetics/

http://www.hgu.mrc.ac.uk/people/r.meehan_researchb.html

Randy Jirtle http://randyjirtle.com/

Transposable Elements: Targets for Early Nutritional Effects on Epigenetic Gene Regulation. Robert A. Waterland and Randy L. Jirtle http://mcb.asm.org/content/23/15/5293.long

Virgin a/a females, 8 weeks of age, were assigned randomly to NIH-31 diet or NIH-31 supplemented with the methyl donors and cofactors folic acid, vitamin B12, choline chloride, and anhydrous betaine

Maternal dietary methyl supplementation and coat color phenotype of Avy/a offspring. Isogenic Avy/a animals representing the five coat color classes used to classify phenotype. The Avy alleles of yellow mice are hypomethylated, allowing maximal ectopic agouti expression. Avy hypermethylation silences ectopic agouti expression in pseudoagouti animals, recapitulating the agouti phenotype.

Hungry Planet by Faith D'Aluisio and Peter Menzel. Shown is the weekly amount of food consumed in different countries. http://www.books4yourkids.com/2012/12/what-world-eats-by-faith-daluisio.html

1. Health, Nutrition, DNA2. History Biochemical Pathways, Vitamins and Omics3. Triage Theory4. Structural Proteins, DNA variations5. Conclusions

James Lind, a British Royal Navy surgeon who, in 1747, identified that a quality in fruit prevented the disease of scurvy in what was the first recorded controlled experiment.

The earliest documented case of scurvy was described by Hippocrates around 400 BC. The term vitamin was derived from "vitamine," a compound word coined in 1912 by the Polish biochemist Kazimierz Funk when working at the Lister Institute of Preventive Medicine. The name is from vital and amine, meaning amine of life, because it was suggested in 1912 that the organic micronutrient food factors that prevent beriberi and perhaps other similar dietary-deficiency diseases might be chemical amines. This proved incorrect for the micronutrient class, and the word was shortened to vitamin.

Kazimierz Funk

A vitamin is an organic compound required by an organism as a vital nutrient in limited amounts. An organic chemical compound (or related set of compounds) is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. http://en.wikipedia.org/wiki/Vitamin

The human disease network http://www.pnas.org/content/104/21/8685.abstract

(b) In the DGN, each node is a gene, with two genes being connected if they are implicated in the same disorder. The size of each node is proportional to the number of disorders in which the gene is implicated (see key). Nodes are light gray if the corresponding genes are associated with more than one disorder class. Genes associated with more than five disorders, and those mentioned in the text, are indicated with the gene symbol. Only nodes with at least one link are shown.

In the HDN, each node corresponds to a distinct disorder, colored based on the disorder class to which it belongs, the name of the 22 disorder classes being shown on the right. A link between disorders in the same disorder class is colored with the corresponding dimmer color and links connecting different disorder classes are gray. The size of each node is proportional to the number of genes participating in the corresponding disorder

Flavor network and the principles of food pairing

Each node denotes an ingredient, the node color indicates food category, and node size reflects the ingredient prevalence in recipes. Two ingredients are connected if they share a significant number of flavor compounds, link thickness representing the number of shared compounds between the two ingredients.

(A) The ingredients contained in two recipes (left column), together with the flavor compounds that are known to be present in the ingredients (right column). Each flavor compound is linked to the ingredients that contain it, forming a bipartite network. Some compounds (shown in boldface) are shared by multiple ingredients. (B) If we project the ingredient-compound bipartite network into the ingredient space, we obtain the flavor network, whose nodes are ingredients, linked if they share at least one flavor compound. The thickness of links represents the number of flavor compounds two ingredients share and the size of each circle corresponds to the prevalence of the ingredients in recipes. (C) The distribution of recipe size, capturing the number of ingredients per recipe, across the five cuisines explored in our study. (D) The frequency-rank plot of ingredients across the five cuisines show an approximately invariant distribution

across cuisines.

Yong-Yeol Ahn,Sebastian E. Ahnert,James P. Bagrow& Albert-László Barabási

Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes http://www.sciencedirect.com/science/article/pii/S0092867412001663

Revolution in Personalized Medicine: First-Ever Integrative 'Omics' Profile Lets Scientist Discover, Track His Diabetes Onset (March 2012) http://www.sciencedaily.com/releases/2012/03/120315123020.htm

Geneticist Michael Snyder, PhD, has almost no privacy. For more than two years, he and his lab members at the Stanford University School of Medicine pored over his body's most intimate secrets: the sequence of his DNA, the RNA and proteins produced by his cells, the metabolites and signaling molecules wafting through his blood.

“A large database with the complete time-dynamic profiles for more individuals that acquire infections and other types of diseases will be extremely valuable in the early diagnostics, monitoring and treatment of diseased states.”

iPOP Goes the World: Integrated Personalized Omics Profiling and the Road toward Improved Health Care http://www.cell.com/chemistry-biology/fulltext/S1074-5521%2813%2900174-9#MainText integrated personal omic profiling (iPOP)

Highlights in iPOP(A) Integration of DNA variants to assess disease risk (RiskGraph, top panel) and a sample pharmacogenome (bottom panel). Arrow heads point in the direction of the change in posttest probability (%).(B) Expression analysis (partial heatmap) of the transriptome and proteome over a time course spanning a respiratory syncytial viral (RSV) infection, with glucose monitoring (bottom, onset of T2D). Genes showing relative change in expression are clustered and represented as a network of inter- and intraconnected pathways: RNA (blue circle), protein (yellow square), and both RNA and protein (green hexagon). An example of a metabolite identified during the time course is also shown (inset panel).

Schematic Representing the Implementation of iPOP for Personalized Medicine(A) Participant tissue sample (e.g., PBMC) is collected, while environment (including diet, exercise, etc.), medical history, and clinical data are recorded. T1 is the first time point.(B) Selected omic analysis involved in a sample iPOP study (Chen et al., 2012).(C) Sample Circos plot (Krzywinski et al., 2009) of DNA (outer ring), RNA (middle ring), and protein (inner ring) data matching to chromosomes.(D) iPOP performed and integrated at multiple time points: T2, T3, T4 (viral infected), and T5 up to Tn states, including disease state(s). Grey and green forms represent a relatively healthy individual and a disease state, respectively.(E) Report data back to genetic counselor and medical practitioner with better informed choices for prevention and/or treatment (matched with pharmacogenetic data), if needed.

1. Health, Nutrition, DNA2. History Biochemical Pathways, Vitamins and Omics3. Triage Theory4. Structural Proteins, DNA variations5. Conclusions

Bruce AmesDr. Ames is a Senior Scientist at Childrens Hospital Oakland Research Institute (CHORI), director of their Nutrition & Metabolism Center, and a Professor Emeritus of Biochemistry and Molecular Biology, University of California, Berkeley.He is a member of the National Academy of Sciences and he was on their Commission on Life Sciences. He was a member of the board of directors of the National Cancer Institute, the National Cancer Advisory Board, from 1976 to 1982. He was the recipient of the General Motors Cancer Research Foundation Prize (1983), the Tyler Environmental Prize (1985), the Gold Medal Award of the American Institute of Chemists (1991), the Glenn Foundation Award of the Gerontological Society of America (1992), the Lovelace Institutes Award for Excellence in Environmental Health Research (1995), the Honda Prize of the Honda Foundation, Japan (1996), the Japan Prize, (1997), the Kehoe Award, American College of Occup. and Environ. Med. (1997), the Medal of the City of Paris (1998), the U.S. National Medal of Science (1998), The Linus Pauling Institute Prize for Health Research (2001), and the American Society for Microbiology Lifetime Achievement Award (2001). His over 540 publications have resulted in his being among the few hundred most-cited scientists (in all fields).

Triage Theory: Metabolism responds to moderate deficiency of an essential vitamin or mineral so that the scarce cofactor is retained (by proteins) for short term survival/reproduction while long term health/longevity proteins associated with aging lose vitamins/minerals and are disabled. 40 essential micronutrients (vitamins/minerals) and mild deficiencies associated with aging (cancer, heart disease). Vitamin K and selenium, are well studied and published examples. In addition, the Institute of Medicine sets the RDA (Recommended Daily Allowance) two standard deviations above EAR (Estimated Average Requirement), most of the US population is below EAR for one or more vitamin/mineral. NHANES database indicates US population: 56% below for magnesium, 12% zinc, 49% vitamin B6 (older women), 16% iron (menstruating women). Low intakes of vitamin D, calcium, potassium, omega-3 fatty acids, and vitamin K.

Deregulated Nutrient Sensing

The somatotrophic axis in mammals comprises the growth hormone (GH), which is produced by the anterior pituitary, and its secondary mediator, insulin-like growth factor 1 (IGF-1), produced in response to GH by many cell types, most notably hepatocytes. The intracellular signaling pathway of IGF-1 is the same as that elicited by insulin, which informs cells of the presence of glucose. For this reason, IGF-1 and insulin signaling are known as the “insulin and IGF-1 signaling” (IIS) pathway. Remarkably, the IIS pathway is the most conserved aging-controlling pathway in evolution, and among its multiple targets are the FOXO family of transcription factors and the mTOR complexes, which are also involved in aging and conserved through evolution Genetic polymorphisms or mutations that reduce the functions of GH, IGF-1 receptor, insulin receptor, or downstream intracellular effectors such as AKT, mTOR, and FOXO have been linked to longevity, both in humans and in model organisms, further illustrating the major impact of trophic and bioenergetic pathways on longevity.Consistent with the relevance of deregulated nutrient sensing as a hallmark of aging, dietary restriction (DR) increases lifespan or healthspan in all investigated eukaryote species, including nonhuman primates

The Hallmarks of Aging. http://www.cell.com/abstract/S0092-8674%2813%2900645-4#MainText

1. Health, Nutrition, DNA2. History Biochemical Pathways, Vitamins and Omics3. Triage Theory4. Structural Proteins, DNA variations5. Conclusions

A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes in a human. For example, two sequenced DNA fragments from different individuals, AAGCCTA to AAGCTTA, contain a difference in a single nucleotide. In this case we say that there are two alleles. As of 26 June 2012, dbSNP listed 53,558,214 SNPs in humans http://en.wikipedia.org/wiki/Single-nucleotide_polymorphism

A SNP is a single-letter change in DNA, part of the natural genetic variation within a population.Image courtesy of Lauren Solomon, the Broad Institute

PMID 19103647] rs12934922 (R267S) and rs7501331 (A379V) double mutant have a reduced catalytic activity of beta-carotene by 57%. Female volunteers carrying the T variant of rs7501331 (379V) had a 32% lower ability to convert Beta-carotene, and those carrying at least one T in both SNPs show a 69% lower ability to convert Beta-carotene into retinyl esters.

rs7501331: the frequency of the wild-type C allele and variant T allele was 76 and 24%, respectively; 56% of the population was CC wild-type genotype, and 39% was heterozygote CT with the TT variant present in 5% of the population.

rs12934922: the frequency of the wild-type A allele and variant T allele was 58 and 42%, respectively; 38% of the population was AA wild-type genotype, 40% was heterozygote AT, and 22% was TT homozygote

[PMID 19557453] beta-Carotene conversion products and their effects on adipose tissue.

[PMID 19844255] Fine mapping and association studies of a high-density lipoprotein cholesterol linkage region on chromosome 16 in French-Canadian subjects.

[PMID 21091228] Genetic variants in BCMO1 and CD36 are associated with plasma lutein concentrations and macular pigment optical density in humans.

[PMID 22113863] Single nucleotide polymorphisms upstream from the beta-carotene 15,15'-monoxygenase gene influence provitamin A conversion efficiency in female volunteers.

“Vitamins” search returns over 500 SNPs and counting

MTRR, Methionine Synthase Reductase, Ile22Met, reduction in enzyme activity, increases in homocysteine.

MTR, Methionine Synthase, Asp919Gly, increased enzyme activity, reduction in homocysteine.

MTHFR, Methylenetetrahydrofolate reductase, Ala222Val, Glu429Ala, reduced enzyme activity, increased homocysteine.

LPL, Lipoprotein Lipase, Ser474Stop, increased LPL levels.

LIPC, Hepatic Lipase, -293G>A (insulin stimulation blunted), -557C>T (diminished activity).

CEPT, Cholesterol Ester Transfer Protein, 279G>A, lower levels of CETP/lower LDL/VLDL levers.

GSTP1, Glutathione-S-Transferase, Ile105Val, Ala114Val, decreased enzyme activity.

GSTM1, GSTT1, Glutathione-S-Transferase, deletions.

CBS, Cystathionine Beta Synthase, 699C>T, increased enzyme activity, lower homocysteine levels.

Cubulin Receptor (B12), Rs11254363.

LRP2 (Megalin/gp330), Rs2544390, serum uric acid (Japanese/alcohol)

This variation accounts for roughly 12% of human genomic DNA and each variation may range from about one kilobase (1,000 nucleotide bases) to several megabases in size. CNVs contrast with single-nucleotide polymorphisms (SNPs), which affect only one single nucleotide base.

Copy-number variations (CNVs)—a form of structural variation—are alterations of the DNA of a genome that results in the cell having an abnormal number of copies of one or more sections of the DNA.

http://en.wikipedia.org/wiki/Copy-number_variation

Evan Eichler http://www.gs.washington.edu/faculty/eichler.htm

http://www.nature.com/nature/journal/v464/n7289/full/nature08516.html

Sequence alignment and domain organization of human thioredoxin reductases and homologus proteins. (A) The sequences of cytosolic (TrxR1; entry: Q16881) and mitochondrial (TrxR2; entry: Q9NNW7) thioredoxin reductases and of thioredoxin glutathione reductase (TrxR3; entry: Q86VQ6) were obtained from Swiss-Prot/TrEMBL protein sequence database and aligned with Clustal W 2.0.10 Multiple Sequence Alignment [197]. Selenocysteine (U) appears as the penultimate amino acid. (B) Domain organization of human TrxR1 (hTrxR1), TrxR2 (hTrxR2), TrxR3 (hTrxR3), E. coli TrxR and human glutathione reductase

(hGR). The different domains are specified below each schematic representation, while in the upper part the motifs of the active centers are reported .

Thioredoxin reductase: A target for gold compounds acting as potential anticancer drugs. http://www.sciencedirect.com/science/article/pii/S0010854509000770

Clustal is a widely used multiple sequence alignment computer program. In bioinformatics, Basic Local Alignment Search Tool, or BLAST, is an algorithm for comparing primary biological sequence information, such as the amino-acid sequences of different proteins or the nucleotides of DNA sequences. A BLAST search enables a researcher to compare a query sequence with a library or database of sequences, and identify library sequences that resemble the query sequence above a certain threshold.

Genetic map of Europe; genes vary as a function of distance http://blogs.discovermagazine.com/gnxp/2008/08/genetic-map-of-europe-genes-vary-as-a-function-of-distance/#.UadHgZyGdsI

Razib Khan, Gene Expression Blog/Discover

Genetic Map of East Asia

http://scienceblogs.com/gnxp/2008/12/07/genetic-map-of-east-asia/

Genetic variation within Africa (and the world)http://blogs.discovermagazine.com/gnxp/2010/08/genetic-variation-within-africa-and-the-world/#.UaeP8JyGdsI

Differences in genetic risk among populations.Each population is ranked by risk, which is denoted by a color. Populations with the greatest risk are bright red, and those with the lowest risk are green. (A) Populations for East Asia and the Americas have lower genetic risk for type 2 diabetes than those from Africa and Europe. Genetic risk differentiation is sharply divided along major population migration events. Type 2 diabetes is represented by 16 SNPs. (B) Genetic risk for biliary liver cirrhosis is represented by 44 SNPs. Genetic risk peaks in East Asia and in the Karitiana population in South America. The background is a public domain world map from NASA Earth Observatory (http://eoimages.gsfc.nasa.gov/images/im agerecords/73000/73909/world.topo.bathy. 200412.3×5400×2700.jpg);an interactive online tool is available at http://geneworld.stanford.edu using Google Maps technology.doi:10.1371/journal.pgen.1003447.g001 Analysis of the Genetic Basis of Disease in the Context of Worldwide Human Relationships and Migration

Atul Buttehttp://buttelab.stanford.edu/

Erik Corona, Rong Chen, Martin Sikora, Alexander A. Morgan, Chirag J. Patel, Aditya Ramesh, Carlos D. Bustamante, Atul J. Butte. (23 May 2013) Analysis of the Genetic Basis of Disease in the Context of Worldwide Human Relationships and Migration. PLoS Genetics, 2013; 9 (5): e1003447 DOI: 10.1371/journal.pgen.1003447

Sequence alignment with predicted secondary structure for vitamin D hydroxylases. Invariant (black-shaded) and partially conserved (green-shaded) residues in mitochondrial (CYP24A1, CYP27A1, CYP27B1) and microsomal (CYP2R1, rat CYP2J3, CYP2D6, CYP3A4) proteins are associated with the heme-binding site (thiolate) and structural motifs such as the ERR triad (not shown). Predicted secondary structures with helices (blue) and β-sheet structures (gold) are shown above the sequence alignments. Missense mutations (red-shaded) associated with cerebrotendinous xanthomatosis (CYP27A1 deficiency) and vitamin D dependency rickets type 1 (CYP27B1 deficiency) are described in Table 1. Sequences were retrieved from Entrez (www.ncbi.nlm.nih.gov/Entrez/index.html) and the Cytochrome P450 Homepage (drnelson.utmem.edu/CytochromeP450.html) and adjusted manually using GeneDoc v2.6 in a larger alignment (not shown) of species homologs and crystal structures, including CYP2B4, CYP2C5, CYP2C8, CYP2C9, CYP3A4, CYP51 (Mycobacterium tuberculosis), CYP119 (Sulfolobus solfactaricus) and P450Bm-3, cam, eryF and terp

Different views of the homology model of CYP24A1. The homology model of CYP24A1 is viewed down the putative substrate access channel (a) and from above the distal heme face (b). The tertiary structure of the heme distal cavity is bordered by the β1 sheet (center, purple), β3a strand (yellow), β5 hairpin (cyan), B -helix (green), F-helix ′(orange) and the loop (center, pink) between the F-helix (orange) and the G-helix (red). Parts of the A- and A -helices (gray) ′are positioned to contact a substrate access channel. The C-helix (purple) is also shown. Traces of other secondary structural elements are also visible in the figure. The model was constructed and energy-minimized using SYBYL6.8.

Enzymes involved in the activation and inactivation of vitamin D http://www.sciencedirect.com/science/article/pii/S0968000404002701

The Multifunctional Properties and Characteristics of Vitamin D-binding Proteinhttp://www.sciencedirect.com/science/article/pii/S1043276000003179

The vitamin D-binding protein gene (DBP) and the albumin family members are linked on human chromosome 4. DBP is encoded by a single gene on human chromosome 4, sublocalized to bands 4q11–q13, and linked to its three other family members (4q11–q22). Recently, this region has been mapped, and this family of genes was found to be linked as shown, with ≈1.5 megabase pairs separating DBP from the ALB gene5. Arrows indicate directions of transcription. Abbreviations: AFM, gene encoding α-albumin/atamin; AFP, gene encoding α-fetoprotein; ALB,

gene encoding albumin.

Amino acid sequence and predicted secondary structure features of human vitamin D-binding protein (DBP) (GC*1S allele). The 458 amino acids of DBP are shown folded into their disulfide-bonded, triple domain structure (indicated on the left). The third domain is truncated in DBP but is full-length in albumin (ALB) and α-fetoprotein (AFP). The smaller circles mark the positions of residues present in ALB and AFP but absent in DBP (Ref. 8). A disulfide bond that forms a loop containing the sterol-binding region (green; residues 35–49), not present in either ALB or AFP, is indicated by the orange line linking residues 13 and 59. All 28 cysteine residues are conserved in all known DBP sequences. The experimentally determined actin-binding domain (yellow; residues 373–403) is also indicated15. A multiple alignment of the six known DBP amino acid sequences was made; namely, human8, rabbit11, rat9, mouse10, turtle12 and chicken13. Only those residues showing identity or conservative substitutions in all six species are shaded (red or pink, respectively). Thus, the figure demonstrates the very high level of homology

among DBP sequences from reptiles to human.

Vitamin D-binding protein also known as gc-globulin (group-specific component) is a protein that in humans is encoded by the GC gene. http://en.wikipedia.org/wiki/Vitamin_D-binding_protein

Retinol-binding proteins (RBP) are a family of proteins with diverse functions. They are carrier proteins that bind retinol. Assessment of retinol-binding protein is used to determine visceral protein mass in health-related nutritional studies. http://en.wikipedia.org/wiki/Retinol_binding_protein

Cubilin (CUBN) acts as a receptor for intrinsic factor-vitamin B12 complexes. The role of receptor is supported by the presence of 27 CUB domains. Cubulin is located within the epithelium of intestine and kidney. Mutations in CUBN may play a role in autosomal recessive megaloblastic anemia

Top: schematic drawing of amino acids contributing to substrate binding in DATAs, BCATs and ADCLs. The external aldimines, which are formed after binding and transimination of the respective substrates with the PLP cofactor of the enzymes, are shown. Blue amino acids are part of binding pocket A and amino acids of binding pocket B are shown in green. The gray shaded circle represents the glycine or valine, depending on the transaminase, that is located behind the carboxyl group. The red threonine residue is important in the catalytic mechanism for shuttling of a proton during the reaction transition state. Bottom: sequence motifs derived from multiple-sequence alignments are given using the same color code, showing that amino acids important for substrate binding in the active site are rather conserved and can be used for a prediction of the substrate specificity of PLP-dependent fold class IV enzymes as well as for the enantiopreference of the transaminases within this fold class

Rational assignment of key motifs for function guides in silico enzyme identification http://www.nature.com/nchembio/journal/v6/n11/full/nchembio.447.html

Identification of key amino acid motifs that allow prediction of function of PLP-dependent fold class IV proteins.

How a protein binds b12: a 3.o angstrom x-ray structure of the b12-binding domains of methionine synthase

The core structure of the cobalamin-binding domain is characterised by a five-stranded alpha/beta (Rossmann) fold, which consists of 5 parallel beta-sheets surrounded by 4-5 alpha helices in three layers (alpha/beta/alpha). Upon binding cobalamin, important elements of the binding site appear to become structured, including an alpha-helix that forms on one side of the cleft accommodating the nucleotide 'tail' of the cofactor. In cobalamin, the cobalt atom can be either free (dmb-off) or bound to dimethylbenzimidazole (dmb-on) according to the pH. When bound to the cobalamin-binding domain, the dimethylbenzimidazole ligand is replaced by the active histidine (His-on) of the DXHXXG motif. The replacement of dimethylbenzimidazole by histidine allows switching between the catalytic and activation cycles. In methionine synthase the cobalamin cofactor is sandwiched between the cobalamin-binding domain and an approximately 90 residues N-terminal domain forming a helical bundle comprising two pairs of antiparallel helices. This N-terminal domain forms a 4-helical bundle cap, in the conversion to the active conformation of this enzyme, the 4-helical cap rotates to allow the cobalamin cofactor to bind the activation domain.

B12-binding domain uses a histidine to bind the cobalt atom of cobalamin cofactors. This histidine is embedded in a DXHXXG sequence, the most conserved primary sequence motif of the domain

Quinone Oxidoreductases and Vitamin K Metabolism http://www.sciencedirect.com/science/article/pii/S0083672907000052

Genotype-phenotype association studies in clinically well characterized patients with inherited bleeding disorders. Prof. Dr. Johannes Oldenburg http://www.herz-kreislauf-netz.de/index.php?id=58&L=1&BF=1

Vitamin Analogs used in cancer (Folate) and blood thinning treatments (vitamin K)

"We estimate that formally integrating genetic testing into routine warfarin therapy could allow American warfarin users to avoid 85,000 serious bleeding events and 17,000 strokes annually. We estimate the reduced health care spending from integrating genetic testing into warfarin therapy to be $1.1 billion annually, with a range of about $100 million to $2 billion.“ http://www.clotcare.com/warfaringenetictesting.aspx

http://snpedia.com/index.php/Rs1800566

rs1800566 (C609T, Pro187Ser) is a snp within NQO1 (NAD(P)H dehydrogenase (quinone 1)). A Ser (T) at this location denotes the NQO1*2 allele.

NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer http://www.nature.com/ng/journal/v40/n7/full/ng.155.html

Coenzyme Q10 supplementation reduces HF admissions and improves survival: Q-SYMBIO"CoQ10 should be considered as a part of the maintenance therapy of patients with chronic heart failure.“ 31 May 2013

Conclusions

1. DNA and nutrients impact health in a diversity of ways2. Triage theory distinguishes short term and long term needs3. Vitamin/Mineral binding domains conserved4. Variations in binding domains lead to differences in requirements5. Multiple proteins impact health including transporters, enzymes

The rs11144870 SNP in the riboflavin kinase (RFK) gene on chromosome 9 was associated with 8-week treatment response (odds ratio (OR)=0.42, P=1.04 × 10−6).

Pharmacogenomics of selective serotonin reuptake inhibitor treatment for major depressive disorder: genome-wide associations and functional genomics

In enzymology, a riboflavin kinase (EC 2.7.1.26) is an enzyme that catalyzes the chemical reaction

ATP + riboflavin --- ADP + FMN

Thus, the two substrates of this enzyme are ATP and riboflavin, whereas its two products are ADP and FMN.

Riboflavin is converted into catalytically active cofactors (FAD and FMN) by the actions of riboflavin kinase (EC 2.7.1.26), which converts it into FMN, and FAD synthetase (EC 2.7.7.2), which adenylates FMN to FAD

In molecular biology, the Acyl-CoA-binding protein (ACBP) is a small (10 Kd) protein that binds medium- and long-chain acyl-CoA esters with very high affinity and may function as an intracellular carrier of acyl-CoA esters. ACBP is also known as diazepam binding inhibitor (DBI) or endozepine (EP) because of its ability to displace diazepam from the benzodiazepine (BZD) recognition site located on the GABA type A receptor. It is therefore possible that this protein also acts as a neuropeptide to modulate the action of the GABA receptor

Acyl-CoA binding protein: “Brain Makes Its Own Version of Valium http://www.sciencedaily.com/releases/2013/05/130530132429.htm

Rs8192506acyl-CoA-binding protein (ACBP) single nucleotide polymorphismsRs2084202Association of acyl-CoA-binding protein (ACBP)

Tocopherol Activity Correlates with Its Location in a Membrane: A New Perspective on the Antioxidant Vitamin E http://pubs.acs.org/doi/abs/10.1021/ja312665r?ref=tw

Vitamin B12 transporter http://en.wikipedia.org/wiki/ATP-binding_cassette_transporter

Intrinsic factor (IF) also known as gastric intrinsic factor (GIF) is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 later on in the small intestine. In humans, the gastric intrinsic factor protein is encoded by the GIF gene.

(1) Dietary vitamin B12 is normally bound to proteins in food and is provided by food products of animal origin.(2) Pepsin and acid pH in the stomach will degrade these food proteins and release vitamin B12.(3) The vitamin B12 that is now free then binds to one of the three vitamin B12 binding proteins, called haptocorrin, which is produced by the salivary glands and the parietal cells in the stomach. In the duodenum the pH is now less acidic and this allows pancreatic proteases to degrade the haptocorrin, and vitamin B12 (both newly ingested and from the bile duct) is released again and binds tightly to Intrinsic Factor produced by parietal cells.(4) In the mucosal cells of the distal ileum the vitamin B12-Intrinsic Factor complex is recognised by special receptors.(5) Vitamin B12 then enters the blood bound to another binding protein, transcobalamin, the complex is known as holotranscobalamin (Active B12). The majority of vitamin B12 (70-80%) in blood is bound to haptocorrin and only a minor proportion (20-30%) is bound to transcobalamin.(6) Holotranscobalamin (Active B12) is the biologically active fraction of vitamin B12 in the blood as it is in only this form that vitamin B12 is delivered to all the cells of the body.(7) Vitamin B12 absorbed in the intestine subsequently gets transported to the liver via the portal system.(8) There is extensive enterohepatic circulation of vitamin B12 and B12 is transported from the liver, via the bile duct, to the duodenum

Table 1. Ligand specificity of LDLR family membersa Ligands Physiological category LDLR family membersb and c RAP Chaperone A,B,C,D,E,H (+) HSP-96 Chaperone B (+) Apolipoprotein E LM, AD A,B,C,D,E,F,J (+) Apolipoprotein B LM A,C (+) β2-Glycoprotein C (+) Apolipoprotein J/clusterin/Sp40,40 LM C,D (+); B (−) Apolipoprotein J-amyloid β AD C (+) Lipoprotein (a) LM A,B,C,D (+) Lipoprotein lipase LM A,B,C,D,F (+) Hepatic lipase LM B (+) Vitellogenin LM G (+) Cubilin LM, VM C (+) α2-Macroglobulin-protease complexes PH B,F (+); C (−) Pro-uPA PH B,C,D (+) UPA-PAI-1 PH B,C,D (+) UPA-protease nexin-1 PH B,D (+) TPA PH B,H (+) TPA-PAI-1 PH B,C (+) Thrombin-PAI-1 PH B (+) Thrombin-protease nexin 1 PH B (+) Thrombin-antithrombin III PH B (+) Thrombin-heparin cofactor II PH B (+) Trypsin-a1-antitrypsin PH B (+) Coagulation factor VIII PH B (+) Coagulation factor Ixa PH B (+) Coagulation factor Xa-TFPI PH B (+) TFPI PH B,D (+) Aprotinin PH C (+) Cathepsin G-α1 antichymotrypsin PH C (+); B (−) Elastase-α1 antitrypsin PH B,C (+) MMP-13 PH B (+) MMP-9 PH B (+) Thrombospondin-1 AG B,C,D (+) Thrombospondin-2 AG B (+) Thrombospondin-2/MMP2 PH, AG B (+) Reelin ND D,F (+) Alzheimer's precursor protein PH B (+) Transcobalamin-vitamin B12 VM C (+) Vitamin D-binding protein VM C (+) Retinol-binding protein VM C (+) Thyroglobulin HM C (+) Parathyroid hormone HM C (+) Insulin HM C (+) Prolactin HM C (+)And more……

Diverse roles for the LDL receptor family http://www.sciencedirect.com/science/article/pii/S1043276001005264

Dudley K. Strickland W. Scott Argraves

The Nutrition Source

http://www.hsph.harvard.edu/nutritionsource/

http://www.hsph.harvard.edu/walter-willett/

Walter Willett, Fredrick John Stare Professor of Epidemiology and NutritionChair, Department of Nutrition, Harvard School of Public Health

In the patients, a characteristic urinary protein profile with increased urinary excretion of vitamin D-binding protein, retinol-binding protein and albumin was associated with absence of, or reduced, proximal tubular endocytic uptake as shown by renal immunohistochemistry.

Renal phenotypic investigations of megalin-deficient patients’: novel insights into tubular proteinuria and albumin filtration. http://ndt.oxfordjournals.org/content/early/2012/10/08/ndt.gfs462.abstract

Concentration-function relations for vitamin C. The solid line represents schematically the amount of vitamin C that will prevent scurvy with a margin of safety, on the basis of guidelines described in the text. The dashed line represents another putative function of vitamin C independent of preventing scurvy. The dotted line represents a putative genetic variation that has reduced maximal function. B: Relation between vitamin C dose and steady state plasma concentration. The relation between vitamin C dose and plasma concentration for men is shown by the solid line (data derived from reference 5-Food and Nutrition Board, Panel on Dietary Antioxidants and Related Compounds. Vitamin C: Dietary Reference Intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington, DC: National Academy Press, 200095–185). The dashed line represents a shift in achieved concentration as a consequence of a putative polymorphism in vitamin C metabolism or transport. “Vitamin C: working on the x-axis” (AJCN 2009) http://ajcn.nutrition.org/content/90/5/1121.full

The Thiamine diphosphate dependent Enzyme Engineering Database: A tool for the systematic analysis of sequence and structure relations http://www.biomedcentral.com/1471-2091/11/9

In molecular biology, the vitamin B12-binding domain is a protein domain which binds to cobalamin (vitamin B12). It can bind two different forms of the cobalamin cofactor, with cobalt bonded either to a methyl group (methylcobalamin) or to 5'-deoxyadenosine (adenosylcobalamin). Cobalamin-binding domains are mainly found in two families of enzymes present in animals and prokaryotes, which perform distinct kinds of reactions at the cobalt-carbon bond. Enzymes that require methylcobalamin carry out methyl transfer reactions. Enzymes that require adenosylcobalamin catalyse reactions in which the first step is the cleavage of adenosylcobalamin to form cob(II)alamin and the 5'-deoxyadenosyl radical, and thus act as radical generators. In both types of enzymes the B12-binding domain uses a histidine to bind the cobalt atom of cobalamin cofactors. This histidine is embedded in a DXHXXG sequence, the most conserved primary sequence motif of the domain. Proteins containing the cobalamin-binding domain include:

nmr structure of glutamate mutase (b12-binding subunit) complexed with the vitamin b12 nucleotide

LDL Receptor Gene Family. Modular Domain Assembly and Pleiotropy. Pleiotropy occurs when one gene influences multiple phenotypic traits.

Differences among individuals for most quantitative or complex traits such as reading ability are distributed as a normal bell-shaped curve. Multiple genes influence complex traits as probabilistic propensities rather than predetermined programmes. Here the different genetic make-up of individuals with respect to two hypothetical genes involved in reading ability is shown for 100 individuals (each person is represented by an oval), with five of these individuals (those on the extreme left) receiving a diagnosis of reading disability. The green ovals indicate that the individual has the disabling variant of one gene and blue ovals denote the disabling variant of the other gene. Neither gene is necessary or sufficient for low scores, even for individuals who have disabling variants of both genes (red ovals). This QTL perspective suggests that genes associated with common disorders such as reading disability may represent the quantitative extreme of the same genes that are responsible for variation throughout the population. http://www.nature.com/nature/journal/v402/n6761supp/full/402c25a0.html

Genes encoding for isocitrate dehydrogenases 1 and 2, IDH1 and IDH2, are frequently mutated in multiple types of human cancer. Mutations targeting IDH1 and IDH2 result in simultaneous loss of their normal catalytic activity, the production of α-ketoglutarate (α-KG), and gain of a new function, the production of 2-hydroxyglutarate (2-HG). 2-HG is structurally similar to α-KG, and acts as an α-KG antagonist to competitively inhibit multiple α-KG-dependent dioxygenases, including both lysine histone demethylases and the ten-eleven translocation family of DNA hydroxylases. Abnormal histone and DNA methylation are emerging as a common feature of tumors with IDH1 and IDH2 mutations and may cause altered stem cell differentiation and eventual tumorigenesis. Therapeutically, unique features of IDH1 and IDH2 mutations make them good biomarkers and potential drug targets.