Biochemistry and Metabolism Flashcards
Describe the metabolism of triglycerides in the context of DKA.
A patient in DKA is deficient in Insulin and so utilises Triglyceride breakdown for energy.
TGs are metabolised to FFA and Glycerol. Glycerol is taken to the liver and phosphorylated to glycerol-3-phosphate by glycerol kinase.
G3P is then converted to dihydroxyacetone phosphate (DHAP) by G3P dehydrogenase, this can be used to produce glucose through gluconeogenesis.
What are the 4 commonly tested Glycogen storage diseases?
(“Very Poor Carbohydrate Metabolism”)
Von-Gierke disease (Type I)
Pompe disease (Type II)
Cori disease (Type III)
McArdle disease (Type V)
What is the deficient enzyme in Von Gierke disease?
What is the clinical presentation?
Patients with Von Gierke disease are deficient in Glucose-6-Phosphatase.
This prevents them metabolises G6P into Glucose; they therefore present with hepatomegaly, hypoglycaemia, and elevated blood lactate, uric acid, TGs, and cholesterol.
What is the deficient enzyme in Pompe disease?
What is the clinical presentation?
Patients with Pompe disease are deficient in acid maltase, a lysosomal glucosidase needed to break down glycogen in lysosomes.
The heart is most affected; cardiomegaly and hypertrophic cardiomyopathy. Often the cause of an infant with a big heart.
Also suffer from hypotonia and exercise intolerance.
What is the deficient enzyme in Cori disease?
What are the clinical manifestations?
Patients with Cori disease have a deficient de-branching enzyme (1,6 glucosidase).
They present similarly to Von Gierke with milder symptoms and normal lactate levels; hepatomegaly, growth retardation, muscle weakness, hypoglycaemia.
What is the deficient enzyme in McArdle disease?
What are the clinical manifestations?
Patients with McArdle disease are deficient in skeletal muscle glycogen phosphorylase (Myophosphorylase).
These patients get muscle cramps and myoglobinuria with strenuous activity. Simple sugars pre-exercise can prevent symtpoms.
What is vitamin B1 otherwise known as?
What is its primary function?
How does deficiency of B1 present?
Thiamine is involved with decarboxylation of a-keto acids in CHO metabolism.
Thiamine deficiency causes Beri-Beri (wet or dry) and also Wernicke-Korsakoff syndrome.
What is vitamin B2 otherwise known as?
What is its primary function?
How does deficiency of B2 present?
Riboflavin is a mitochondrial electron carrier (FMN, FAD).
Deficiency causes angular cheilosis, stomatitis, and glossitis.
Normocytic anaemia may also occur.
What is vitamin B3 otherwise known as?
What is its role?
How does B3 deficiency manifest?
Niacin is a constituent of NAD+ and NADP+ in electron transfer reactions.
Deficiency causes pellagra (diarrhoea, dementia, dermatitis) and peripheral neuropathy.
What is Hartnup disease?
Hartnup disease is an autosomal recessive disorder leading to a deficiency of neutral AA transporters in the PCT and on enterocytes.
It leads to loss of tryptophan, and therefore niacin and so causes Pellagra-like symptoms.
What is vitamin B5 otherwise known as?
What is its role?
How does vitamin B5 deficiency manifest?
Pantothenic acid is an essential component of coenzyme A and fatty acid synthase.
Deficiency causes dermatitis, enteritis, alopecia, and adrenal insufficiency.
What is vitamin B6 otherwise known as?
What is its role?
How does vitamin B6 deficiency manifest?
Pyridoxine is a cofactor in transamination, decarboxylation, and for glycogen phosphorylase. It is also neccessary for the synthesis of multiple neurotransmitters.
Deficiency is hellish (6); seizures, neuropathies, anaemias.
What is vitamin B7 otherwise known as?
What is its role?
How does B7 defiency manifest and what is the frequent cause of B7 deficiency?
Biotin is a cofactor for carboxylation enzymes.
Avidin in egg whites binds Biotin, as do some antibiotics.
Deficiency causes dermatitis, alopecia, enteritis.
What is vitamin B9 otherwise known as?
What is its role?
How does B9 deficiency manifest?
Folate is converted to tetrahydrofolic acid and is used as a coenzyme for 1-carbon methylation. It is crucial for synthesis of nitrogenous bases in DNA and RNA.
Deficiency causes macrocytic anaemia, hypersegmented neutrophils, glossitis, and NO NEUROLOGICAL SYMPTOMS (cf cobalamin).
What is vitamin B12 also known as?
What is its role?
How does defiency of B12 manifest?
Which serum levels are raised with B12 deficiency?
Cobalamin is used as a cofactor for methionine synthase and methylmalonyl-CoA mutase. It is important for DNA synthesis.
Deficiency causes macrocytic anaemia, hypersegmented neutrophils, parasthesias, and sub acute combined degeneration (dorsal columns, LCSTs, and SCTs).
Increased serum homocysteine and methylmalonic acid.
Describe the adenoma to carcinoma sequence in relation to colonic polyps:
- APC inactivation
- Methylation abnormalities and COX2 overexpression
- K-ras activation and p53 inactivation
- Unregulated cell proliferation.
What is the specific defect in nucleotide excision repair in patients with xeroderma pigmentosum?
What are the other enzymes involved?
UV exposure creates thymine dimers.
Endonuclease recognises this (deficient in XP) and the DNA is cleaved.
DNA polymerase and DNA ligase then repair the strand.
List the immuno-suppressive, antineoplastic, and antibacterial medications that interfere with nucleotide synthesis:
(“LeftT on the M5, RigHt on the M6”)
Leflunomide
Trimethoprim
Methotrexate
5-fluorouracil
Ribavirn
Hydroxyurea
Mycophenalate
6-Mercaptopruine
How do Methotrexate and Trimethoprim work?
Both inhibit dihydrofolate reductase, in humans and bacteria respectively.
What causes Lesch-Nyhan syndrome?
Lesch-Nyhan syndrome is caused by a defect in the purine salvage pathway. Absent Hypoxanthine guanine phosphoribosyltransferase results in excess uric acid and de novo purine synthesis.
What are the characteristic features of Lesch-Nyhan syndrome?
(HGPRT)
Hyperuricaemia
Gout
Pissed-off (aggression and self mutilation)
Retardation
dysTonia
Where do Fluoroquinolones work?
Fluoroquinolones inhibit prokaryotic topoisomerase II
(aka DNA gyrase)
Which 3 key enzymes is Thiamine a cofactor for?
(“think ATP”)
alpha-ketoglutarate dehydrogenase
transketolase
pyruvate dehydrogenase
What are the roles of Hexokinase and Glucokinase?
How do they differ in regard to Km, Vmax, effect of Insulin, and feedback from G6P?
Both catalyse phosphorylation of Glucose into Glucose-6-phosphate; Hexokinase sequesters glucose in the tissues, Glucokinase in the liver.
Hexokinase has a higher affinity (lower Km) and reduced capacity (lower Vmax) than Glucokinase. It is not induced by Insulin and it is negatively fed-back on by G6P.
Once Glucose is “trapped” in the cell as G6P, what is the next catabolic step and why is it important?
G6P becomes Fructose-6-phosphate.
This is catalysed by Phosphofructokinase and is the rate limiting step on the way to Pyruvate.
Arsenic inhibits one of the co-enzymes for the Pyruvate dehydrogenase complex.
Which one?
And what are the others?
(The Lovely Coenzymes For Nerds)
Thiamine
Lipoic acid (affected by arsenic)
CoA (Pantothenic acid)
FAD (Riboflavin)
NAD+ (Niacin)
What are the findings with a pyruvate dehydrogenase deficiency?
What is the treatment?
Affected infants have neurological deficits, lactic acidosis, and increased serum alanine (shunted to the Cahill cycle).
The treatment is based on increasing Ketogenic AAs (Leucine and Lysine) to utalise that pathway.
What are the 4 pathways available to Pyruvate?
- Cahill shunt to Alanine
- Pyruvate carboxylase to Biotin
- Pyruvate dehydrogenase to the TCA
- Lactate dehydrogenase to Lactate (Cori cycle)
Which complexes of the Electron transport chain do the following drugs inhibit?
Antimycin
Rotenone
Cyanide
Carbon Monoxide
Rotenone = Complex 1
Antimycin = Comlex 3
Cyanide = Complex 4
CO = Complex 4
Fructose is to Aldolase B as…?
Galactose is to Uridyltransferase.
(Fructose intolerance and Classic Galactosaemia)
What is the point of the urea cycle?
AA metabolism results in the formation of common metabolites (pyruvate, acetyl-CoA) which serve as metabolic fuels, BUT, excess nitrogen is generated, and its gotta go somewhere…
The urea cycle converts excess N into Urea for excretion in the kidneys.
Mitochondrial carbamoyl phosphate is the product of CO2 and NH3; list the steps from this point to Urea…
(“Ordinarily, Careless Crappers Are Also Frivolent About Urination”)
What is Ornithine Transcarbamylase Deficiency?
How does it present?
OTD is an AR disorder causing problems with the urea cycle.
Findings include increased orotic acid in blood and urine, hyperammoniaemia.
What is Phenylketonuria?
Which AA becomes essential?
AR disease due to reduced phenylalanine hydroxylase.
Tyrosine becomes essential.
What is Maple Syrup Urine Disease?
Which AAs need restriction?
(“I Love Vermont maple syrup)
AR disease caused by deficiency in branched-chain-a-ketoacid dehydrogenase. Babie’s urine smells like burnt syrup. Vomiting and poor feeding.
Isoleucine
Leucine
Valine
How does Homocysteinuria present?
HOMOCYstinuria
Homocyteinuria
Osteoporosis
Marfanoid habitus
Occular changes (down and in lens sublux)
CVS disease
kYphosis
retardation
What are the two enzymes that may be affected causing homocysteinuria?
Methionine synthase
Cystathionine synthase.
Haxagonal crystals in the urine are pathgnomonic for?
What is the treatment?
Cystinuria.
Hereditary defect in PCT transporters for Cystine, Ornithine, Lysine, and Arginine (COLA)
Treat with urinary alkalinization and chelating agents.
What is the most common Sphingolipidoses?
What are the classical findings on exam/histo?
What is the treatment?
Gaucher disease.
Hepatosplenomegaly, pancytopenia, osteoporosis, bone crises.
Gaucher cells (crumpled tissue paper) on histo.
Treat with recombinant glucocerebrosidase.
What enzyme is deficient in Tay-Sachs disease?
What is the presentation?
What is the accumulated substrate?
Hexosaminidase A
Progressive neurodegeneration, cherry red spot, lysosomes with onion skin.
GM2 ganglioside accumulates.
Which enzyme is deficient in Niemann-Pick disease?
What is the classical presentation?
What feature is present that is not present with Tay-Sachs?
Sphingomyelinase
Progressive neurodegeneration, cherry red spot on macula.
HEPATOSPLENOMEGALY (not present with T-S).
What are the Citrate and Carnitine shuttles used for?
Both are mitochondrial membrane shuttles.
Citrate transfers Citrate from the mitochondria to the cytoplasm for synthesis of fatty acids.
Carnitine shuttles Fatty Acyl-CoA into mitochondria for ß-oxidation.
What are two causes of hypoketotic hypoglycaemia?
How should they be treated/managed?
- Systemic primary Carnitine deficiency
- MCFA Acyl-CoA dehydrogenase deficiency.
Both cause lethargy, seizures, coma. Treat by avoiding fasting.
What are the 4 types of Familial Dyslipidaemia?
Which are associated with increased MI risk?
Which are associated with increased pancreatitis risk?
Type I = Hyperchylomicronaemia (panc)
Type II = Familial hypercholesterolaemia (MI)
Type II = Dyslipoproteinaemia (MI)
Type IV = Hypertriglyceridaemia (panc)
What causes Familial Hypercholesterolaemia?
Absent or defective LDL receptors.
Raised LDL, cholesterol, and sometimes VLDL.
Where do the following biochemical processes occur?
Fatty acid synthesis
Pentose phosphate pathway
Beta-oxidation
Carboxylation of pyruvate
Glycolysis
The TCA cycle?
Beta-oxidation, the TCA cycle, and the carboxylation of pyruvate (gluconeogenesis) all occur in the mitochondria.
The enzymes for glycolysis, fatty acid synthesis, and the pentose-phosphate pathway reside in the cytosol.
List 3 hormones that utilise the Tyrosine Kinase second-messenger system.
Insulin
Insulin-like Growth Factor
Platelet derived Growth Factor
List 4 hormones/molecules that utilise the JAK-STAT second-messenger system:
Growth hormone
EPO
Cytokines
GCSF
List 5 hormones that utilise the adenylate cyclase second-messenger system.
What is the second messenger in this set up?
Glucagon
TSH
PTH
ACTH
ADH
Protein kinase A.
List 4 hormones that function by binding to G-protein coupled receptors that activate Phospholipase C.
GnRH
TRH
Angiotensin II
ADH (V1 receptor)
