First Aid Biochem No pics Just Text PDF

Preview

Summary

Written format of Biochem First aid 2020 textbook....

Description

BIOCHEM Chromatin – DNA phosphate is negative. Histone Lysine and Arginine is positive DNA and histone synthesis during S phase Histone acetylaton = Remove histone + charge = relaxed DNA = more transcription Thyroid hormone receptor acetylation = change thyroid hormone synthesis Dysregulated acetylation in Huntington’s disease CPS2 – is cyTWOsol, used in pyrimidine base production CPS1 = m1tochondria for urea cycle Orotic Aciduria – impaired UMP synthase Leflunomide – inhibit dihydroorate dehydrogenase. Decrease pyrimidine synth. 5-Fluorouracil/capaecitabine –Forms 5-F-dUMP which inhibits thymidylate synthase. Decreases dTMP. 6-mercaptopurine/Azathioprine – inhibit purine synthesis Mycophenolate/ribavirin – inhibit inosine monophosphate dehydrogenase Hydroxyurea – inhibit ribonucleotide reductase. No dUDP. Methotrexate aka MTX/Trimethoprim aka TMP/Pyrimethamine – inhibit dihydrofolate reductase. Reuces deoxythymidine monosphosphate dTMP. No THF formed. (MTX for humans, TMP for bacteria, pyrimethamine for protozoa) Pyrimidine base production requires aspartate Purine base production requires aspartate, glycine, glutamine, THF Adenosine deaminase deficiency – AR. Can’t degrade adenosine and deoxyadenosine. Inc dATP = low RNR activity = low DNA precursors in cells = low lymphocytes. Lymphotoxocity. SCID. “bubble boy” Lesch-Nyhan Syndrome – XR. No HGPRT. No purine salvage. Excess uric acid. Increased guanine and hypoxanthine. Hyperuricemia, Gout, Pissed off, Retard, Dystonia. Self mutilate. Orange cystals in diaper. Mycrocytosis Tx. Allopurinal/Febuxostat HGPRT converst hypoxanthine  IMP, guanine  GMP Cladribine/Pentostatin - inhibits ADA Allopurinol/Febuxostat = inhibits XO Urate oxidase = rasburicase Degenerate/Redundant genetic code feature expections: AUG (methionine) + UGG (tryptophan) DNA Replication TATA box -origin of rep and promoters Eukaryotes: Irinotecan/topotecan inhibits topoisomerase I. Etoposide/Teniposide inhibit TOP II. Prokaryotes: Fluoroquinolones inhibit topoisomerase II (DNA Gyrase) and TOP IV DNA Polymerase III – prok only. has 5’-3’ synthesis. Proofread 3’-5’ exonuclease. Drugs w/ 3’OH cause chain termination DNA Polymerase I – prok only. degrade RNA primer. Replace with DNA. 5’-3’ exonuclease to remove RNA primer DNA ligase – joins okazaki fragments Telomerase – euk only. RNA dep DNA polymerase. Add TTAGGG to 3’ end. Upreg in cancer. Downreg in aging & progeria Bloom Syndrome – X helicase. BLM gene mutation. DNA repair NHEJ – some DNA may be lost. Defective in Ataxia-Telangiectasia HR – Defective in breast/ovarian cancers with BRCA1 mutation and Fanconi Anemia (bone marrow failure). Accurate w/o loss of nucleotides Nucleotide excision repair – specific endonucleases. X in Xeroderma Pigmentosum. Can’t repair pyrimidine dimers from UV exposure. G1 phase Xeroderma pigmentosum – X nucleotide excision repair. Present with dry skin, photosensitivity, skin cancer Base excision repair – “GEL PLease” – Glycosylase, Endonuclease, Lyase, Polymerase, Ligase. Throughout cell cycle. Repair spontaneous/toxic deamination Base Specific Glycolysase removes altered bases + create AP site AP Endonuclease cleaves 5’ end AP Lyase cleaves 3 end DNA Polymerase B fills gap DNA ligase seals Mismatch Repair – unmethylated strand is new strand. S phase. Defect in Lynch Syndrome and HNPCC. Silent 200 repeats) = postpubertal macroorchidism (enlarged testes), long face with large jaw, large everted ears, autism, MVP, hypermobile joints, self-mutiliation (don’t confuse with Lesch-Nyhan Syndrome). Anticipation - increased severity and early onset with each generation seen in trinucleotide repeat diseases Trinucleotide repeat diseases: Huntingtons CAG AD Caudate low Ach and GABA Myotonic Dystrophy CTG AD Cataract Toupee Gonadal Atrophy Fragile X Syndrome CGG XD Chin, Giant Gonads Friedreich Ataxia GAA AR Ataxic GAAit Trisomy 21 – 95% meiotic nondisjunction during meiosis I. 1:1500 45 yo mothers. 4% Robertsonian translocation Ch. 14/21. MC* viable chromosomal disorder. MC* genetic intellectual disability. 1st trimester US – increased nuchal translucency & hypoplastic nasal bone. Markers – high hCG, high inhibin (HI). Duodenal atresia, Hirschsprung Disease, ASD, Brushfield spots (Whitish spots at the periphery of the iris). Early onset Alzheimer (Ch 21 is amyloid precursor protein APP). Inc. risk of AML/ALL.. “5 A’s of Down Syndrome”. 1:700 Trisomy 18 – Edwards. Overlapping Fingers. PRINCE: Prominent occiput, rocker bottom feet, Intell dis, nondisjunction, clenched fists, low ears. Micrognathia, congential heart disease, omphalacele, myelomeningocele. Death 1yr. 1:8000. All Low prenatal screening markers Trisomy 13 – Patau. Severe intel dis, rocker bottom feet, clef lip and palate, holoprosencephy, cutis aplasia, PKD, polydactyly, omphalacele. Death by 1yr. Defect in fusion of prechordal mesoderm  midline defects. 1:15,000 Nondisjunction in Meiosis I = 2 trisomy and 2 monosomy Nondisjunction in Meiosis II = 2 normal, 1 monosomy, 1 trisomy 1st trimester screening – 21 high bhcG, low PAPP-A. 18 and 13 both low 2nd trimester: low BhCG, low Inhibin A, Low Estriol, Low AFP = Trisomy 18 2nd trimester: no anything = Trisomy 13. 2nd trimester: high BhCG, high inhibin A, low estriol, low AFP = Trisomy 21 Genetic Disroders by chromosome 3 – vHL disease, RCC 4 – ADPKD (PKD2), achondroplasia, Huntington Disease 5 – Cri-du-Chat Syndrome, FAP 6 – HFE 7 – Williams Syndrome, CF 9 – Friedreich Ataxia, TSC1 11 – Wilm’s Tumor, MEN1, B-globin gene defects (Sickle Cell Disease, B-thalassemia) 13 – Patau Syndrome, Wilson Disease, RB1, BRCA2 15 – Prader-Willi Syndrome, Angelman Syndrome, Marfan Syndrome 16 – ADPKD (PKD1), a-globin gene defects (a-thalassemia), TSC2 17 – NF Type 2, BRCA1, TP53 (Li-Fraumeni Syndrome) 18 – Edwards Syndrome 21 – Down Syndrome 22 – NF Type 2, DiGeorge Syndrome (22q11) X – Fragile X Syndrome, X linked agammaglpobulinemia, Klinefelter Syndrome (XXY) Robertsonian Translocation – 21, 22, 13, 14, 15. 2 acrocentric long arms fuse with 2 short arms. Unbalanced translocations – miscarriage, still birth, Down Syndrome, Patau syndrome Cri-Du-Chat Syndrome – Cat cry. Congential deletion of short arm. Microcephaly, moderate/severe intellectual disability, high pitched crying, epicanthal folds, VSD. Ch 5. 46,XX or XY,5pWilliams Syndrome – congential microdeletion of long arm ch 7. Deletion includes elastin gene. Elfin face, intel dis. Hypercalcemia, well developed verbal skills, extrem friendliness with strangers, supravalvular aortic stenosis, renal artery stenosis (cardiovascular problems)

Essential FA – polyunsat FA. Can’t be synth by body. Come from diet. Nuts/seeds/plant oils/seafood. Linoleic acid = omega-6 = metab to arachidonic acid = leukotriene and prostaglandins precurosor. Linolenic acid = omega-3 = cardioprotective and antihyperlipidemic Fat Soluble vitamins – Vit ADEK. Ileum & pancreas absorbs. Accumulate in fat. Toxicity higher. Deficiency caused by mineral oil intake or malabs syndrome with steatorrhea (CF and Celiac Disease) Water Soluble Vitamins – B1-12, Vit C. Easily wash out body except B12&B9. B12 in liver 3-4 years, B9 in liver 3-4months. B deficiencies cause dermatitis, glossitis, diarrhea. Can be Coenzymes (ascorbic acid) or precursors to coenzymes (FAD, NAD+) B1 = Thiamine: TPP B2 = Riboflavin: FAD, FMN B3 = Niacin: NAD+ B5 = Pantothenic Acid: COA B6 = Pyridoxine: PLP B7 = Biotin B9 = Folate B12 = Cobalamin C = Ascorbic Acid Vitamin A – retinal, retinol, retinoic acid. Antioxidant. Retinal in visual pigments. Stored in live stellate cells. Part of Rhodopsin in Retina. Essential for normal differentiation of epithelial cells into specialized tissue (pancreatic cells, mucus secreting cdlls). Prevents squamous metaplasia. Retinol = Vitamin A used topically for wrinkles and acne. In liver & leafy vegetables. Use to treat Vit. A deficient measles to improve outcomes. Oral isotretinoin treat severe cystic acne. All-TRANS retinoic acid treat APML. Topical treats oral hairy leukoplakia (EBV). Tx Retinitis Pigmentosa Vit A deficiency = night blindness (nyctalopia, dry scaly skin (xerosis cutis), dry eyes (Xerophthalmia), corneal squamous metaplasia = Bitot Spots (keratin debris, foamy appearance on conjunctiva. Corneal degeneration aka keratomalacia. Immunosuppression. Penumonia, pancreatic exocrine duct, growth retard, kidney stones Vit A Excess - Acute toxicity = nausea, vomiting, increased ICP (vertigo, blurred vision). Chronic Toxicity = alopecuam, dry skin, scaliness, hepatic toxicity & enlargement, antralgia, idiopathic intracranial HTN aka Pseudotumor cerebri swelling of optic N. Teratogenic (clef palate, cardiac abnormalities), if prescribe isotretinoin must have neg. pregnancy test & use two forms of contraception. Hyperkeratosis. Vitamin B1 – Thiamine. Thiamine pyrophosphate (TTP), cofactor for dehydrogenase enzymes = Branched chain ketoacid dehydrogenase – makes Leucine/Isoleucine/Valine Defect = Maple Syrup Urine Disease, alpha-ketoglutarate dehydrogenase (TCA Cycle) – betw aKG to Succinyl-CoA, Pyruvate Dehydrogenase (links glycolysis to TCA cycle), Transketolase (HMP shunt), makes R5P to G3P&F6P Deficiency – Impaired glucose breakdown = ATP depletion worsened by glucose infusion. Brain and heart affected first. Chronic alcohol overuse or malnutrition pt. give thiamine BEFORE dextrose to reduce risk of precipitating Wernicke Encephalopathy. Dx: Vit B1 admin results in incr RBC transketolase activity Disorders: Wernicke enceph.: acute, revers. life threat. neurologic condition. confusion, ophthalmoplegia/Nystagmus, Ataxia. Korsakoff Syndrome: Amnestic. chronic alcohol overuse, confab, personality changes, permanent memory loss. Wernicke-Korsakoff Syndrome: damage ant and medial dorsal nucleus of thalamus, mamm. bodies Dry beriberi: Peripheral polyneuropathy, symmetric muscle wasting, Wet beriberi: High output cardiac failure (DCM). Edema. HF Vitamin B2 – Riboflavin. FAD and FMN for 2ATP. Cofactors in redox rxns. Succinate dehydrogenase in TCA cycle. FMN for Complex I and FAD for Complex II of ETC Cause Def: malnutrition, chronic alcoholism, liver disease, gut malabsorption Deficiency – Stomatitis, Angular Cheilosis, Magenta Tongue, Seborrheic Dermatitis, Corneal Vascularization & Keratitis, Normocytic Normchromic anemia Cheliosis = inflammation of lips, scaling and fissures at the corners of the mouth Vitamin B3 – Niacin, Nicotinic Acid. NAD+ & NADP+ for 3ATP. Redox rxns. Cofactor for dehydrogenases. Derived from Tryptophan. Synthesis requires Vit B2 and B6. Treats Dyslipidemia (lowers VLDL & triglyc, increase HDL). NADP+ required for fat/steroids, alcohol metab via cyp450, regenerate glutathione, heme. NAD+ required for Glycolysis, TCA, Beta-oxid. Cause Def: Corn as primary food staple, Chronic Alcohol, malabs, Hartnup Disease (AR) – enterocytes and renal PCT cells can’t absorb Tryptophan defective neutral a.a. transporter. Carcinoid Syndrome, TB Drug Isoniazid use (lowers Vit B6). Deficiency – Glossitis. Pellagra = 4Ds: diarrhea, dementia, dermatitis (C3/C4 dermatome broad collar rash = Casal necklace), death. Hyperpigmentation of sun exposed limbs. Cerebellar ataxia begins in early childhood. Headaches, Confusion, Irritability, Insomnia, Hallucinations, Encephalopathy, Peipheral Neuropathy Excess – Hyperglycemia, Hyperuriciemia, Podagra (gout), Facial Flushing (induced by prostaglandins, not histamine. Avoid with aspirin with the niacin).

Malignant Carcinoid Syndrome – increased tryptophan metabolism promotes serotonin synthesis instead of Vit B3. diarrhea, flushing, dyspnea, and wheezing. Endocardial fibrosis that especially affects the right heart. Tricuspid insufficiency and/or pulmonary stenosis. Symptoms of right-sided heart failure Hartnup Disease – AR. Def. of neutral aa transporters (like tryptophan) in proximal renal tubular cells and enterocytes = neutral aminoaciduria, decreased absorption from gut = low tryptophan conversion to niacin = pellagra like symp. Tx = high protein diet and nicotinic acid. Vitamin B5 – Pantothenic Acid. Coenzyme A – cofactor for acyl transfers and FA synthase. Make Acetylcholine, acetylate histones to promote gene expression, make corticosteroids. Def. – Dermatitis, Enteritis, Alopecia, Adrenal insufficiency (can’t make enough corticosteroids). Burning Feet Syndrome Vitamin B6 – Pyridoxine. Pyridoxal Phosphate (PLP), Cofactor in transamination (ALT and AST), decarboxylation reactions, glycogen phosphorylase (rate limiting step in glycogen degradation). Synthesis of glutathione, cystathione, heme, niacin, histamine, melatonin, histamine, NT (serotonin, epineprhine, norepinephrine, dopamine, GABA). Cause of def: Isoniazid, OCP, hydralazine, penicillamine Deficiency – stomatitis, glossitis, cheliosis. convulsions, hyperirritability, peripheral neuropathy, microcytic sideroblastic anemia (from impaired hemoglobin synthesis and iron excess). Seizures & Seborrheic Dermatitis. Excess – Peripheral Neuropathy, Photosenstivity, Dermatosis Vitamin B7 – Biotin. Cofactor for carboxylation of enzymes (1carbon group transfers): 1. Pyruvate Carboxylase (gluconeogenesis: Pyruvate to Oxaloacetate) 2. Acetyl-CoA carboxylase (FA synthesis: acetyl-CoA to malonyl CoA). 3. Propionyl-CoA Carboxylase (FA oxidation: priopionyl-CoA to methylmalonyl-CoA  branched chain a.a. catabolism & VOMIT pathway) Deficiency – Relatively rare. Myalgia, perioral dermatitis, enteritis – anorexia/diarrhea, alopecia. Neuropysch dysfxn. Children developmental delay. Lactic Acidosis. Causes include long term antibiotic use or excess raw egg whites (Avidin). Biotinidase Deficiency – inborn error where iotin can’t be recycled or released from food during digestion Vitamin B9 – Folate. Tetrahydrofolic Acid (THF). Leafy Green Vegetables. Produced by Gut Flora. Jejunum absorbs. Small reserve in liver. Coenzyme for 1 carbon transfer/methylation reactions. DNA and RNA nitrogenous base synthesis – purine and thymine nucleotides. Req to metabolize homocysteine (B9 def means homocysteine goes up) Causes of def - Chronic alcohol overuse and pregnancy, Phenytoin, Sulfonamides, Methotrexate & Pyrimethamine & Trimethoprim inhibit dihydrofolate reductase which regenerates THF Deficiency – Macrocytic megaloblastic anemia, hypersegmented polymorphonuclear cells PMNs, atrophic glossitis, no neurologic symptoms unlike B12 def. Labs: inc. homocysteine, normal methylmalonic acid Supplemental folic acid atleast 1 month before conception or early pregnancy to reduce neural tube defects. Vitamin B12 – Cobalamin. Cofactor for Methionine Synthase (transfers CH3 groups as methylcobalamin for Homocystein  Methionine) and methylmalonyl-CoA mutase (methylmalonyl CoA to succinyl CoA) in odd chain FA breakdown (VOMIT Pathway). DNA synthesis (5methylTHF  THF). Animal Products. Synthesized only by microorganisms. Several years of storage in liver. Req to make myelin. Causes of def – Malabsorption from Sprue, Enteritis, Diphyllobothrium Latum, Achlorhydria (PPI or H2 Blockers), bacterial overgrowth, alcohol overuse. Lack of intrinsic factor (pernicious anemia or gastric bypass surgery), absent terminal ileum from surgical resection or Crohns, Metformin, Veganism. Pancreatic insufficiency. Deficiency – macrocytic megaloblastic anemia, hypersegmented PMN, atrophic glossitis, paresthesias, Subacute Combined Degeneration of posterior columns, lateral corticospinal tracts, spinocerebellar tracts bc abnormal myelin. increased serum homocysteine and methylmalonic acid levels, 2’ folate deficiency. Prolonged def = irreversible nerve damage. B9 supplementation can mask hematologic symp of B12 def but not neurologic symp. Reversible dementia. Peripheral neuropathy VOMIT pathway – Valine, Odd chaing FA, Methionine, Isoleucine, Threonine SCID – degen. dorsal column, LCST, spinocerebellar tract Dorsal columns – proprioceptions and vibration LCST – spastic weakness & hyperreflexia Spinocerebellar tract - ataxia Vitamin C – Ascorbic Acid. Antioxidant. Facilitates iron absorption by reducing it to Fe2+ state. Tx methemoglobinemia along with methylene blue. Vit C + Lysine + Methionine  carnitine. Metabolize prostaglandins. Promote Nitric oxide synthesis. Hydroxylation of proline & lysine in collagen synthesis. Dopamine B-hydroxylase to convert Dopamine to NE. Fruits & Vegetables. Ancillary treatment for methemoglobinemia by Fe3+ to Fe2+. Deficiency – Scruvy = swollen gums, easy bruising, petechiae, hemarthrosis, poor wound healing, perifollicular and subperiosteal hemorrhages, corkscrew hair in hyperkeratotic follicles, periodontal disease. Weak immune system. From tea and toast diet. Anemia. Children have bony deformitites, hemorrhages, usbperiosteal and joint hematomas. Excess – Nausea, Vomit, Diarrhea, Fatigue, Calcium Oxalate Nephrolithiasis. Increases iron toxicity in predisposed individuals. Worsens hemochromatosis and transfusion related iron overload Vitamin D – D3 (cholecalciferol) from exposure of skin (stratum basale) to sun, ingestion of fish, milk, plants. D2 (ergocalciferol) from ingestion of plants, fungi, yeasts. Both converted to 25-OH D3 (storage form) in liver and to the active form 1,25-(OH)2 D3

(calcitriol) in kidney via 1ahydrodylase. Inc intestinal absorption of Ca2+ and PO43–. Bone mineralization at low levels. Bone resorption at higher levels. 1,25-(OH)2D3 feedback inhibits its own production. PTH inc Ca2+ reabsorption and dec PO43– reabsorption in the kidney. Rickets in children (deformity, such as genu varum “bowlegs”), osteomalacia in adults (bone pain and muscle weakness), hypocalcemic tetany. Caused by malabsorption, sun exposure, poor diet, chronic kidney disease (CKD), advanced liver disease. Give oral vitamin D to breastfed infants. Darker skin and prematurity predispose to deficiency. Williams Syndrome = hypercalcemia bc increased sensitivity to Vitamin D. Hypophosphatemic Rickets – Vit D receptor mutated XD. Chyvostek Sign cheek hypocalcemia. Trousseau bp cuff hypocalcemia. Vit D excess - Hypercalcemia, hypercalciuria, loss of appetite, stupor. Seen in granulomatous diseases (activation of vitamin D by epithelioid macrophages). Vitamin E – alpha tocopherol, antioxidant protect cell membranes from oxidative damage, prevent oxidation of LDL, slow decline in Alzheimer patients, Def causes: fat malabs, abetalipoproteinemia and ataxia with vitamin E defiency (AVED) genetic disorders, Def – hemolytic anemia, ancanthocytes (spur cells), skeletal myopathy (muscle weakness), spinocerebellar tract degen, posterior column degen loss of position and vibratory sense, loss of DTR, infertility, reduced serum phospholipids. Neurologic presentation may appear similar to vitamin B12 deficiency, but without megaloblastic anemia, hypersegmented neutrophils, or increased serum methylmalonic acid levels. Excess – good for nonalcoholic fatty liver disease and age related macular degeneration. Bad because hemorrhagic stroke in adults, necrotizing enterocolitis in infants. High-dose supplementation may alter metabolism of vitamin K (enhanced anticoagulant effects of warfarin) Vitamin K - Includes phytomenadione, phylloquinone, phytonadione, menaquinone. Activated by epoxide reductase (VKOR) to the reduced form. Cofactor for the γ-carboxylation of glutamic acid residues in proteins for blood clotting. Synthesized by intestinal flora. Neonatal hemorrhage with inc PT and a inc PTT but normal bleeding time (neonates have sterile intestines and are unable to synthesize vitamin K). Can also occur afer prolonged use of broad-spectrum antibiotics. K is for Koagulation. Necessary for the maturation of clotting factors II, VII, IX, X, and proteins C and S. Warfarin inhibits vitamin K– dependent synthesis of these factors and proteins. Not in breast milk; “breast-fed infants Don’t Know about vitamins D and K”. Neonates are given vitamin K injection at birth to prevent hemorrhagic disease of the newborn. Intracranial bleeding in newborn without IM Vit K injection. Tx parenteral vitamin K and FFP or PCC. Tx patient with Warfarin overdose with vit k Zinc – zinc fingers in transcription factor motif. Def = delayed wound healing, suppressed immunity, male hypogonadism, decreased adult hair, dysgeusia, anosmia. Acrodermatitis enteropathica is a defect in intestinal zinc absorption. (1) skin inflammation with pimples (pustular dermatitis) occurring around the mouth and/or anus, (2) diarrhea, a...