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Metabolism, Metabolism, rate-determining enzymes of metabolic…
Metabolism
Metabolism
lysosomal storage disease
Tay-Sachs disease:
progressive neurodegeneration(進行性神経変性), developmental delay, cherry-red spot on macula
Hexosaminidase A
Fabry disease
peripheral neuropathy, angiokeratomas, hydohidrosis, renal failure, cardiovascular disease
α-galactosidaseA
Metachromatic leukodystrophy(異染性白質変性症)
demyelination
arylsulfataseA
Krabbe disease
neuropathy
galactocerebrosidase
Gaucher disease(ゴーシュ病)
most common
Gaucher cell, hepatosplenomegaly, pancytopenia, bone crises
Glucocerebrocidase
Niemann-Pick disease
lipid-laden macrophage, neurodegeneration, hepatosplenomegaly
sphingomyelinase
fabry, Hunter: XR, それ以外:AR
Hurler syndrome, Hunter syndrome
amino acid derivatives
Tryptophan→Niacin→NAD/NADP, →Serotonin→Melatonin
Phe→Tyr→Dopa→Dopamine→NE→epi
PKU(phe---Tyr), albinism(DOPA---melanin), Alkaptonuria(Homogentisic acid---maleyacetoacetic acid)
Histidine→Histamine
Glycine→porphyrin→Heme
Gultamate→GABA,Glutathione
Arginine→Creatine, Urea, Nitric acid
glycogen storage disease(糖原病)
at least 15 types
periodic acid-Schiff stain
Von Gierke disease (type1): Glucose-6-phosphatase
Pompe disease (type2): α1,4glucosidase
Cori disease type3): α1,6glucosidase
McArdle syndrome(type5): glycogen phosphorylase(in skeletal muscle)
Lipid transport
interstinal cell→thoracic duct(胸管)→subclavian vein→-chylomicron→hepatocyte
→VLDL→adipocyte
→VLDL→IDL→hepaocyte→LDL→peripheral cell
key enzyme
hepatic lipase:degrade TG(in IDL)
hormon-sensitive lipase: degrade TG(in adipocyte)
Lecithin-cholesterol acyltransferase: plasma cholesterolのエステル化
Lipoprotein lipase: degrade TG(chylomicron,VLDL)
pancreatic lipase: degrade TG in small intestine
apolipoprotein
E: remnant uptake(chylomicron, VLDL, IDL, HDL)
A-1: activate LCAT(degrade TG in chylomicron, VLDL) (HDL)
C-2: catalyze cleavage(chylomicron, VLDL, HDL)
B-48: mediate chilomicron secretion into lymphatics(chylomicron)
B-100: bind LDL receptor(VLDL, IDL, LDL)
function
Cholesterol: maintain cell membrane, synthesize bile acid, steroid and vitamin D
Chylomicron: dietary TG to peripheral tissue, deliver cholesterol to liver (chylomicron remnant), secreted by intestinal epithelial cell
VLDL: hepatic TG to peripheral tissue, secreted by liver
IDL: degradation of VLDL, deliver TG and cholesterol to liver
LDL: deliver hepatic cholesterol to peripheral tissue,
HDL: deliver cholesterol to liver, repository for apoC,E, secreted by liver intestine, Alcohol→↑
abetalipoproteinemia(無βリポタンパク血症)
AR
chylomicron, VLDL, LDL absent (deficiency of apoB-48,100)
malabsorption, steatorrhea, retinitis pigmentosa(網膜色素変性症), spinocerebellar degeneration, progressive ataxia, acanthocytosis(有棘赤血球増加)
familial dyslipidemias
1:AR, chylomicron, TG, cholesterol
2: AD, a---LDL, cholesterol, b---LDL,VLDL, cholesterol
3: AR, VLDL, chylomicron
4: AD, VLDL, TG
disorder
phenylketonuria
↓phenylalanine hydroxylase, tetrahydrobiopterin cofactor
tyrosine become essential
↑phenylalanine→excess phenyl ketone in urine
intellectual disability, growth retardation, seizure, fair complexion(色白), eczema(湿疹), musty body odor(カビ臭)
treatment: ↓phenylalanine and ↑tyrosine in diet
maternal PKU: in infant, microcephaly(小頭症), intellectual disability
AR, 1/10000
maple syrup urine disease
brocked degradation of branched amino acid(Isoleusine, Leusine, Valine)
CNS defect, intellectual disability, death
AR
alkaptonuria
deficiency of homogentisate oxidase(tyrosine to fumarate)
pigment
AR, benign
homocystinuria
AR
Cystathionine synthase deficiency, or ↓affinity of cystathionine synthase, or methionine synthase deficiency
homocysteine in urine, osteoporosis, marfanoid habitus, ocular change, cardiovascular effect, kyphosis(脊柱後湾症)
cystinuria(シスチン尿症)
prevent reabsorption of cystine, ornithine,lysine, arginine (in PCT and intestinal)
hexagonal cystine stone
AR, 1/7000
glucose→(Aldose reductase)sorbitol→(sorbitol dehydrogenase)fructose
defect cause osmotic damage
liver, ovary, seminal vesicles have both enzyme
lens primarily has aldose reductase
retina, kidney, schwann cell only have aldose reductase
amino acid
only L-amino acid
essential
phenylalanine, leucine, valine, isoleucine, threonine, histidine, tryptophan, lysine, methionine
acidic
aspartic acid, glutamic acid
basic
arginine, histidine, lysine
glycogen
branch--α1,6bond, linkage--α1,4bond
glycogenolysis→G1P→G6P(in skeletal muscle, exercise)
glycogen phosphorylaseがブランチを4つ残す→4-α-D-glucanotransferaseが3つとる→α-1,6-glucosidaseが残りをとる
limit dextrinは1-4個のブランチ
fatty acid
synthesis: citrate→(citrate shuttle)→Acetyl-CoA→Malonyl CoA→Fatty acid
degradation: fatty acid+CoA→fatty acyl CoA→(carnitine shuttle)→β-oxidation(to acetyl-CoA)→Ketone body, TCA cycle
synthesis(mitochondria→cytosol, in liver,mammary gland, adipose tissue)
systemic 1 carnitine deficiency
medium-chain acyl-CoA dehydrogenase deficiency
fuel use
protein=4kcal
alcohol=7kcal
fatty acid=9kcal
fasting and starvation
fed state: glycolysis and aerobic respiration(insulin→storage of lipid, protein, glycogen)
fasting state: glycogenolysis, gluconeogenesis, adipose release of FFA(Glucagon and epinephrine→use of fuel)
starvation days1-3: hepatic glycogenolysis, adipose release of FFA, use FFA, gluconeogenesis from lactate and alanine(peripheral tissue), glycerol and propionyl-CoA(adipose tissue)
day3: vital protein degradation
lactase deficiency
brush border
unable to digest into glucose
GI disorder
Urea cycle
excess nitrogen is converted to urea and excreted by kidney
carbamoyl phosphate, (ornithine)---citruline, (aspartate)---argininosuccinate---(fumarate), arginine---urea, ornithine
ornithine transcarbamylase deficiency
XR, unable to eliminate ammonia, ↑orotic acid, hyperammonemia
transport of ammonia by alanine
alanine: muscle to liver
glucose: liver to muscle
lactate: muscle to liver
hyperammonemia
deplete GABA
inhibition of TCA cycle
flapping tremor(羽ばたき振戦), slurring of speech(ろれつが回らない), somnolence(眠気), vomiting, cerebral edema
glycogen regulation
glucagon, epi→cAMP→PKA→glucogen phosphorylase kinase→glycogen phosphorylase
epi→calcium→glyzogen phosphorylase kinase→glycogen phosphorylase
insulin→(protein phosphatase→)glycogen synthase
ketone body
starvation,diabetic ketoacidosis, alcoholism→ketone body蓄積
production: HMG-CoA lyase
cholesterol synthesis: HMG-CoA reductase
disorder of fructose metabolism
essential fructosuria(本態性フルクトース尿症)
defect in fructokinase
AR
milder symptom
hereditary fructose intolerance(遺伝性フルクトース不耐症)
defect in aldolaseB
AR
F1P accumulate
hypoglycemia, jaundice,cirrhosis, vomiting
disorder of galactose metabolism
galactokinase deficiency
classic galactosemia
defect in galactose-1-phosphate uridyltransferase
AR
failure to thrive, jaundice,hepatomegaly, cataracts, intellectual disability
rate-determining enzymes of metabolic processes(律速酵素)
Glycolysis(解糖)
phosphofructokinase-1(PFK-1)
AMP, F-2,6-BP→↑
ATP, citrate→↓
Gluconeogenesis(糖新生)
fluctose-1,6-bisphosphatase
citrate→↑
AMP, F-2,6-BP→↓
TCA cycle
isocitrate dehydrogenase
ADP→↑
ATP,NADH→⁻
Glycogenesis(グリコーゲン合成)
glycogen synthase
Glycogenolysis
glycogen phosphorylase
HMP shunt(ペントースリン酸経路)
glucose-6-phosphate dehydrogenase
De novo pyrimidine/purine synthesis
Carbamoyl phosphate synthase2/ glutamine-PRPP amidotransferase
urea cycle
carbamoyl phosphate synthase
fatty acid synthesis
Acetyl-CoA carboxylase
fatty acid oxidation
carnitine acyltransferase
ketogenesis
HMG-CoA synthase
cholesterol synthesis
HMG-CoA reductase
pathway
carriers
ATP---P group
NADH, NADPH, FADH2---electron
NAD---catabolic
NADPH---anabolic( steroid, fatty acid synthesis)
anabolic, respiratory burst, cytochrome P-450 system, Glutathione reductase
CoA, lipoamide---acyl group
biotin---CO2
tetrahydrofolate---1-carbon unit
SAM---CH3
TPP---aldehydes
pyruvate dehydrogenase complex
linking glycolysis and TCA
active in fed state
pyruvate+NAD+CoA→acetyl-CoA+CO2+NADH
cofactor: thiamine pyrophosphate(B1), lipoic acid, CoA, FAD, NAD:
activated by: ↑↑NAD/NADHratio, ADP,Ca
arsenic inhibit lipoic acid
deficiency
X-linked
Neurologic defect, lactic acidosis
HMP shunt
provide a source of NADPH
in cytoplasm
G6P→R5P,2NADPH,CO2(glucose-6-P dehydrogenase)
defect---hemolytic anemia,
XR, Heinz body, Bite cell
R5P⇄F6P,R5P,Glyceraldehyde-3-phosphate
H2O2などのフリーラジカルを除去できないため障害が生じる
ATP production
one glucose→32 net ATP(heart, liver, ie. malate-aspartate shuttle
one glucose→30 ATP(muscle, ie. glycerol-3-phosphate shuttle
anaerobic→2 ATP
arsenic cause 0 ATP glycolysis
pyruvate metabolism
alanin(alanin aminotransferase)
oxaloacetate(pyruvate carboxylase)
Acetyl-CoA(pyruvate dehydrogenase)
lactate(lactic acid dehydrogenase)---major in (RBC, WBC, kidey medulla, lens, testes, cornea)
TCA cycle
pyruvate→acetyl-CoA produce 1NADH and 1CO2
3NADH,1FADH2,2CO2,1GTP per acetyl CoA
10ATP(NADH--2.5,FADH2--1.5)
in mitochondria
Glycolysis regulation
Glucose+2P+2ADP+2NAD→2pyruvate+2ATP+2NADH+2H+2H2O
require ATP
Glucose→Glucose-6P (hexokinase/glucokinase)(G6P, F6P→↓↓)
F6P→F1,6BP (phosphofructokinase)(AMP,F-2,6-BP→↑↑, ATP,citrate→↓↓)
regulation by F-2,6-BP
Fasting→↑glucagon→↑FBPase-2,↓PFK-2, less glycolysis, more gluconeogenesis
Fed→↑insulin→↓FBPase-2,↑PFK-2, more glycolysis, less gluconeogenesis
produce ATP
1,3-BPG⇄3-PG(phosphoglycerate kinase)
phosphoenolpyruvate→Pyruvate(pyruvate kinase) (F-1,6-BP→↑,ATP,alanin→↓)
poison
electron transport inhibitor: cyanide, carbon monoxide, azide
ATP syhthase inhibitor: Oligomyein
Uncoupling agent: 2,4-dinitrophenol, aspirin, thermogenin
hexokinase vs glucokinase
glucokinase( in liver, βcell in pancreas)
↑Km, ↑Vmax, induced by insulin, low affinity, high capacity(代謝能)
hexokinase
下Km,↓Vmax, feedbackあり, high affinity, low capacity
oxidative phosphorylation
malate-aspartate/ glycerol-3-phosphate shuttle
NADHやFADH2からHを膜間腔へくみ出して流す力でATPを合成する
gluconeogenesis
irreversible enzyme
pyruvate carboxylase(pyruvate→oxaloacetate
phosphoenolpyruvate carboxykinase(oxaloacetate→phosphoenolpyruvate)
F-1,6-BPase( F-1,6-BP→F-6-P)
G-6-Pase(G6P→glucose)
enzyme term
kinase: transfer of phosphate group
phosphorylase: add phosphate without ATP
phosphatase: remove phosphate
dehydrogenase: oxidation-reduction reaction
hydroxylase: adds hydroxyl group
carboxylase: transfer CO2 group
mutase: relocate functional group
synthase/synthetase: join two molecule
metabolism site
mitochondria
β-oxidation, acetyl-CoA production, TCA cycle, oxidative phosphorylation, ketogenesis
cytoplasm
glycolysis, HMP shunt, synthesis of steroid, protein, fatty acid, cholesterol, nucleotide
Both
heme synthesis, urea cycle, gluconeogenesis