1
Q
what are the cofactors of the pyruvate dehydrogenase complex?
A
thiamin (B1), Lipoic acid, coA (B5)/patotenic acid, FAD (B2, riboflavin), NAD (B3, niacin),
2
Q
electron tranport chain, what happens at the diff complexes?
A
complex 1: NAD, Complex2/ succinate dehydrogenase: FAD, CompleX 3: Fe
ide inhihits
3
Q
g6PD deficiency
A
impairment of glutathione reduction, leads to heinz bodies—bite cells
4
Q
go up on the y-axis
A
vmax is going down
5
Q
when you move left on the x-axis
A
the km is going down, affinity is going up
6
Q
competitive inhib
A
no change in vmax, no change in y-axis,
km goes up, affinity goes down, going right of x-axis
7
Q
noncompetitive inhib.
A
vmax is going down, going up on the y-axis
no change in km, no change in x-axis
8
Q
Activators (more Enzyme)
A
vmax is going up, down on the y-axis,
no change km, no change in x-axis
9
Q
DNA methylation
A
Changes the expression of a DNA segment without changing the sequence. Involved with aging, carcinogenesis, genomic imprinting, transposable element repression, and X chromosome inactivation (lyonization).DNA is methylated in imprinting.
Methylation within gene promoter (CpG islands) typically represses (silences) gene transcription.
CpG methylation makes DNA mute
10
Q
Histone methylation
A
Histone methylation mostly makes DNA mute.
11
Q
Histone deacetylation
A
Removal of acetyl groups —->tightened DNA coiling—-> decreases transcription.
12
Q
Purines
A
Purines (A,G)—2 rings.
Pure As Gold
13
Q
Pyrimidines
A
Pyrimidines (C,U,T)—1 ring.
CUT the pyramid
14
Q
THYmin
A
Thymine has a meTHYl
15
Q
C-G
A
C-G (3H bonds) bonds are like Crazy Glue.”
16
Q
Amino acids necessary for PURine synthesis
A
(cat s PURr until they GAG): Glycine Aspartate Glutamine
17
Q
Deamination reactions:
A
Cytosine—>uracil
Adenine—>hypoxanthine
Guanine—>xanthine
5-methylcytosine—>Thymine
18
Q
Various immunosuppressive, antineoplastic, and antibiotic drugs function by interfering with nucleotide synthesis
A
eg.
19
Q
Pyrimidine synthesis:
A
Leflunomide: inhibits dihydroorotate dehydrogenase
5-fluorouracil (5-FU) and its prodrug capecitabine: form 5-F-dUMP, which inhibits thymidylate synthase ( dTMP)
20
Q
Purine synthesis:
Medication mech.
A
6-mercaptopurine (6-MP) and its prodrug azathioprine: inhibit de novo purine synthesis
Mycophenolate and ribavirin: inhibit inosine monophosphate dehydrogenase
21
Q
Purine and pyrimidine synthesis:
A
Hydroxyurea: inhibits ribonucleotide reductase
Methotrexate (MTX), trimethoprim (TMP), and pyrimethamine: inhibit dihydrofolate reductase ( deoxythymidine monophosphate [dTMP]) in humans, bacteria, and protozoa, respectively
22
Q
Purine and pyrimidine synthesis:
A
Hydroxyurea: inhibits ribonucleotide reductase
Methotrexate (MTX), trimethoprim (TMP), and pyrimethamine: inhibit dihydrofolate reductase ( deoxythymidine monophosphate [dTMP]) in humans, bacteria, and protozoa, respectively
23
Q
carbamoyl phosphate synthetase
A
CPS1 = m1tochondria (urea cycle)
CPS2 = cyTWOsol
24
Q
Adenosine deaminase deficiency
A
ADA is required for degradation of adenosine and deoxyadenosine.
One of the major causes of autosomal recessive SCID.
Severe combined immuodeficiency
25
Lesch-Nyhan syndrome
Defective purine salvage due to absent HGPRT, which converts hypoxanthine to IMP and guanine to GMP.
```
HGPRT:
Hyperuricemia
Gout
Pissed off (aggression, self-mutilation)
Red/orange crystals in urine
Tense muscles (dystonia)
```
Treatment: allopurinol or febuxostat (2nd line).
26
DNA replication
Occurs in 5'--->3′ direction (“5ynth3sis”)
27
Origin of replication
AT-rich sequences (such as TATA box regions) are found in promoters and origins of replication.
28
DNA topoisomerases
Creates a single- (topoisomerase I) or
double- (topoisomerase II) stranded break in the helix to add or remove supercoils (as needed due to underwinding or overwinding of DNA).
In eukaryotes: irinotecan/topotecan inhibit topoisomerase (TOP) I, etoposide/teniposide inhibit TOP II. In prokaryotes: fluoroquinolones inhibit TOP II (DNA gyrase) and TOP IV.
29
Primase
Makes an RNA primer on which DNA polymerase III can initiate replication.
30
DNA polymerase III
Prokaryotes only. Elongates leading strand by adding deoxynucleotides to the 3′ end. Elongates lagging strand until it reaches primer of preceding fragment.
DNA polymerase III has 5′--->3′ synthesis and proofreads with 3′---->5′ exonuclease.
Drugs blocking DNA replication often have a modified 3′ OH, thereby preventing addition of the next nucleotide (“chain termination”).
31
DNA polymerase I
Prokaryotes only. Degrades RNA primer; replaces it with DNA.
Same functions as DNA polymerase III, also excises RNA primer with 5′---->3′ exonuclease
32
Telomerase
Eukaryotes only. A reverse transcriptase (RNA-dependent DNA polymerase) that adds DNA (TTAGGG) to 3′ ends of chromosomes to avoid loss of genetic material with every duplication. Often upregulated in cancer, downregulated in aging and progeria.
Telomerase TAGs for Greatness and Glory
33
DNA repair
Double strand
Nonhomologous end joining
Brings together 2 ends of DNA fragments to repair double-stranded breaks.
Defective in ataxia-telangiectasia. Homology not required. Some DNA may be lost.
34
DNA repair
Double strand
Homologous recombination
Requires 2 homologous DNA duplexes. A strand from damaged dsDNA is repaired using a complementary strand from intact homologous dsDNA as a template.
Defective in breast/ovarian cancers with BRCA1mutation and in Fanconi anemia.
Restores duplexes accurately without loss of nucleotides
35
DNA repair
Single strand
Nucleotide excision repair
Specific endonucleases release the oligonucleotides containing damaged bases; DNA polymerase and ligase fill and reseal the gap, respectively. Repairs bulky helix-distorting lesions.Occurs in G1 phase of cell cycle.
Defective in xeroderma pigmentosum (inability to repair DNA pyrimidine dimers caused by UV exposure). Presents with dry skin, photosensitivity, skin cancer.
36
DNA repair
Single strand
Base excision repair
Base-specific Glycosylase removes altered base and creates AP site (apurinic/apyrimidinic). One or more nucleotides are removed by AP-Endonuclease, which cleaves 5′ end.
AP-Lyase cleaves 3′ end. DNA Polymerase-β fills the gap and DNA ligase seals it.Occurs throughout cell cycle.
Important in repair of spontaneous/toxic deamination.“GEL Please.”
37
DNA repair
Single strand
Mismatch repair
Mismatched nucleotides in newly synthesized (unmethylated) strand are removed and gap is filled and resealed.Occurs predominantly in S phase of cell cycle.
Defective in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC])
38
DNA repair
Single strand
Mutations in DNA
Degree of change: silent << missense < nonsense < frameshift.
Single nucleotide substitutions are repaired by DNA polymerase and DNA ligase.
Types of single nucleotide (point) mutations:
Transition—purine to purine (eg, A to G) or pyrimidine to pyrimidine (eg, C to T).
Transversion—purine to pyrimidine (eg, A to T) or pyrimidine to purine (eg, C to G).
39
Silent mutation
Codes for same (synonymous) amino acid; often involves 3rd position of codon (tRNA wobble).
40
Missense mutation
Results in changed amino acid (called conservative if new amino acid has similar chemical structure). Examples: sickle cell disease (substitution of glutamic acid with valine)
41
Nonsense mutation
Results in early stop codon (UGA, UAA, UAG). Usually generates nonfunctional protein. Stop the nonsense!
42
Frameshift mutation
Deletion or insertion of any number of nucleotides not divisible by 3----> misreading of all nucleotides downstream. Protein may be shorter or longer, and its function may be disrupted or altered. Examples: Duchenne muscular dystrophy, Tay-Sachs disease.
43
Splice site mutation
Retained intron in mRNA ---->protein with impaired or altered function. Examples: rare causes of cancers, dementia, epilepsy, some types of β-thalassemia, Gaucher disease, Marfan syndrome.
44
Lac operon
Classic example of a genetic response to an environmental change. Glucose is the preferred metabolic substrate in E coli, but when glucose is absent and lactose is available, the lac operon is activated to switch to lactose metabolism.
Mechanism of shift:
Low glucose----> increases adenylate cyclase activity---> generation of cAMP from ATP---> activation of catabolite activator protein (CAP)---> increasease in transcription.
High lactose--->unbinds repressor protein from repressor/operator site ---> increase transcription
45
Promoter
Site where RNA polymerase II and multiple other transcription factors bind to DNA upstream from gene locus (AT-rich upstream sequence with TATA and CAAT boxes, which differ between eukaryotes and prokaryotes).
Promoter mutation commonly results in dramatic in level of gene transcription.
46
Enhancer
DNA locus where regulatory proteins (“activators”) bind, increasing expression of a gene on the same chromosome.
Enhancers and silencers may be located close to, far from, or even within (in an intron) the gene whose expression they regulate.
47
Silencer
DNA locus where regulatory proteins (“repressors”) bind, decreasing expression of a gene on the same chromosome.
48
RNA processing (eukaryotes)
Initial transcript is called heterogeneous nuclear RNA (hnRNA). hnRNA is then modified and becomes mRNA.
mRNA is transported out of nucleus to be translated in cytosol.
mRNA quality control occurs at cytoplasmic processing bodies (P-bodies), which contain exonucleases, decapping enzymes, and microRNAs; mRNAs may be degraded or stored in P-bodies for future translation.
Poly-A polymerase does not require a template.
AAUAAA = polyadenylation signal.
The following processes occur in the nucleus:
Capping of 5′ end (addition of 7-methylguanosine cap)
Polyadenylation of 3′ end (∼ 200 A’s----->poly-A tail)
Splicing out of introns
Capped, tailed, and spliced transcript is called mRNA
49
RNA polymerases
Eukaryotes
RNA polymerase I makes rRNA, the most common (rampant) type; present only in nucleolus.
RNA polymerase II makes mRNA (massive), microRNA (miRNA), and small nuclear RNA (snRNA).
RNA polymerase III makes 5S rRNA, tRNA (tiny).
No proofreading function, but can initiate chains. RNA polymerase II opens DNA at promoter site.
I, II, and III are numbered in the same order that their products are used in protein synthesis: rRNA, mRNA, then tRNA.
α-amanitin, found in Amanita phalloides (deat h cap mushrooms), inhibits RNA polymerase II. Causes dysentery and severe hepatotoxicity if ingested.
Actinomycin D, also called dactinomycin, inhibits RNA polymerase in both prokaryotes and eukaryotes.
50
RNA polymerases
| Prokaryotes
1 RNA polymerase (multisubunit complex) makes all 3 kinds of RNA.
Rifamycins (rifampin, rifabutin) inhibit DNA-dependent RNA polymerase in prokaryotes.
51
Helicase
Unwinds DNA template at replication fork. Helicase halves DNA.
Deficient in Bloom syndrome (BLM gene mutation).
52
Splicing of pre-mRNA
Part of process by which precursor mRNA (pre-mRNA) is transformed into mature mRNA.
Alterations in snRNP assembly can cause clinical disease; eg, in spinal muscular atrophy, snRNP assembly is affected due to SMN protein congenital degeneration of anterior horns of spinal cord symmetric weakness (hypotonia, or “floppy baby syndrome”).
Anti-U1 snRNP antibodies are associated with SLE, mixed connective tissue disease, other rheumatic diseases
53
Alternative splicing
Alternative splicing can produce a variety of protein products from a single hnRNA (heterogenous nuclear RNA) sequence (eg, transmembrane vs secreted Ig, tropomyosin variants in muscle, dopamine receptors in the brain, host defense evasion by tumor cells).
54
tRNA Structure
75–90 nucleotides, 2º structure, cloverleaf form, anticodon end is opposite 3′ aminoacyl end. All tRNAs, both eukaryotic and prokaryotic, have CCA at 3′ end along with a high percentage of chemically modified bases. The amino acid is covalently bound to the 3′ end of the tRNA. CCA Can Carry Amino acids.
T-arm: contains the TΨC (ribothymidine, pseudouridine, cytidine) sequence necessary for tRNA-ribosome binding. T-arm Tethers tRNA molecule to ribosome.
D-arm: contains Dihydrouridine residues necessary for tRNA recognition by the correct aminoacyl-tRNA synthetase.
D-arm allows Detection of the tRNA by aminoacyl-tRNA synthetase. Attachment site: 3′-ACC-5′ is the amino acid ACCeptor site
55
mRNA stop codons
UGA, UA A, UAG.
UGA = U Go Away.
UA A = U Are Away.
UAG = U Are Gone
56
Protein synthesis
Initiation
Energy
ATP—tRNA Activation (charging).
| GTP—tRNA Gripping and Going places (translocation).
57
Elongation
APE
Think of “going APE”:
A site = incoming Aminoacyl-tRNA.
P site = accommodates growing Peptide.
E site = holds Empty tRNA as it Exits
58
Termination
Eukaryotic release factors (eRFs) recognize the stop codon and halt translation ---->completed polypeptide is released from ribosome. Requires GTP.
Shine-Dalgarno sequence—ribosomal binding site in prokaryotic mRNA. Enables protein synthesis initiation by aligning the ribosome with the start codon so that code is read correctly.
59
Posttranslational modifications
Trimming
Trimming
Removal of N- or C-terminal propeptides from zymogen to generate mature protein (eg, trypsinogen to trypsin).
Covalent alterations Phosphorylation, glycosylation, hydroxylation, methylation, acetylation, and ubiquitination.
Chaperone protein
Intracellular protein involved in facilitating and maintaining protein folding. In yeast, heat shock proteins (eg, HSP60) are constitutively expressed, but expression may increase with high temperatures, acidic pH, and hypoxia to prevent protein denaturing/misfolding.
60
Cell cycle phases is regulated by?
Checkpoints control transitions between phases of cell cycle. This process is regulated by cyclins, cyclin-dependent kinases (CDKs), and tumor suppressors. M phase (shortest phase of cell cycle) includes mitosis (prophase, prometaphase, metaphase, anaphase, telophase) and cytokinesis (cytoplasm splits in two). G1 and G0 are of variable duration.
61
Cyclin-dependent kinases
Constitutively expressed but inactive when not bound to cyclin.
62
Cyclin-CDK complexes
Cyclins are phase-specific regulatory proteins that activate CDKs when stimulated by growth factors.
The cyclin-CDK complex can then phosphorylate other proteins (eg, Rb) to coordinate cell cycle progression. This complex must be activated/inactivated at appropriate times for cell cycle to progress
63
Tumor suppressors
p53---->p21 induction---->CDK inhibition---->Rb hypophosphorylation (activation)---->G1-S progression inhibition.
Mutations in tumor suppressor genes can result in unrestrained cell division (eg, Li-Fraumeni syndrome).
Growth factors (eg, insulin, PDGF, EPO, EGF) bind tyrosine kinase receptors to transition the cell from G1 to S phase.
64
I-cell disease
N-acetylglucosaminyl-1-phosphotransferase
inclusion cell disease/mucolipidosis type II)—inherited lysosomal storage disorder (autosomal recessive); defect in N-acetylglucosaminyl-1-phosphotransferase----> failure of the Golgi to phosphorylate mannose residues ( mannose-6-phosphate) on glycoproteins ---->enzymes secreted extracellularly rather than delivered to lysosomes --->lysosomes deficient in digestive enzymes---->build-up of cellular debris in lysosomes (inclusion bodies). Results in coarse facial features, gingival hyperplasia, corneal clouding, restricted joint movements, claw hand deformities, kyphoscoliosis, and plasma levels of lysosomal enzymes. Often fatal in childhood.
65
Signal recognition particle (SRP)
Abundant, cytosolic ribonucleoprotein that traffics polypeptide-ribosome complex from the cytosol to the RER.
Absent or dysfunctional SRP----> accumulation of protein in cytosol.
66
Vesicular trafficking proteins
COPI: Golgi---->Golgi (retrograde); cis-Golgi---->ER.
COPII: ER---->cis-Golgi (anterograde).
“Two (COPII) steps forward (anterograde); one (COPI) step back (retrograde).”
Clathrin: trans-Golgi---->lysosomes; plasma membrane----->endosomes (receptor-mediated endocytosis [eg, LDL receptor activity]).
67
Peroxisome
Membrane-enclosed organelle involved in:
β-oxidation of very-long-chain fatty acids (VLCFA) (strictly peroxisomal process)
α-oxidation of branched-chain fatty acids (strictly peroxisomal process)
Catabolism of amino acids and ethanol
Synthesis of cholesterol, bile acids, and plasmalogens (important membrane phospholipid, especially in white matter of brain)
Zellweger syndrome—autosomal recessive disorder of peroxisome biogenesis due to mutated PEX genes. Hypotonia, seizures, hepatomegaly, early death.
Refsum disease—autosomal recessive disorder of α-oxidation---->buildup of phytanic acid due to inability to degrade it. Scaly skin, ataxia, cataracts/night blindness, shortening of 4th toe, epiphyseal dysplasia. Treatment: diet, plasmapheresis.
Adrenoleukodystrophy—X-linked recessive disorder of β-oxidation due to mutation in ABCD1gene----->VLCFA buildup in adrenal glands, white (leuko) matter of brain, testes. Progressive disease that can lead to adrenal gland crisis, progressive loss of neurologic function, death
68
Proteasome
Barrel-shaped protein complex that degrades damaged or ubiquitin-tagged proteins. Defects in the ubiquitin-proteasome system have been implicated in some cases of Parkinson disease.
69
Kartagener syndrome
Autosomal recessive dynein arm defect----> immotile cilia --->dysfunctional ciliated epithelia.
Findings: developmental abnormalities due to impaired migration and orientation (eg, situs inversus, hearing loss due to dysfunctional eustachian tube cilia); recurrent infections (eg, sinusitis, ear infections, bronchiectasis due to impaired ciliary clearance of debris/pathogens); infertility ( risk of ectopic pregnancy due to dysfunctional fallopian tube cilia, immotile spermatozoa). Lab findings: nasal nitric oxide (used as screening test)
70
Collagen synthesis and structure
Hydroxylation—hydroxylation (“hydroxCylation”) of specific proline and lysine residues. Requires vitamin C; deficiency --->scurvy
71
Glycolysis regulation, key enzymes
REqUIRE ATP:
Glucose----------------->Glucose-6 P Hexokinase/glucokinase
Glucose-6 -P ⊝ hexokinase.
Fructose-6-P ⊝ glucokinase.
Fructose-6-P----> Fructose-1,6-BP Phosphofructokinase-1(rate-limiting step)
AMP ⊕, fructose-2,6-bisphosphate ⊕.
ATP ⊝, citrate ⊝.
PRODUCE ATP:
1,3-BPG-------------> 3-PG
Phosphoglycerate kinase
Phosphoenolpyruvate-->Pyruvate
Pyruvate kinase
Fructose-1,6-bisphosphate ⊕.ATP ⊝, alanine ⊝,glucagon ⊝
72
Regulation by fructose-2,6-bisphosphate
Fructose bisphosphatase-2 (FBPase-2)
FaBian the Peasant (FBP) has to work hard when starving.
Fasting state: increasede glucagon------> incresease cAMP-----> increase protein kinase A-------> increases FBPase-2------>decreases PFK-2, less glycolysis, more gluconeogenesis
phosphofructokinase-2 (PFK-2)
Prince FredericK(PFK) works only when fed.
Fed state: increased insulin-----> decreases cAMP----> decreases protein kinase A FBPase-2, increases PFK-2, more glycolysis, less gluconeogenesis.
73
Pyruvate dehydrogenase complex deficiency
Causes a buildup of pyruvate that gets shunted to lactate (via LDH) and alanine (via ALT). X-linked.
FINDINGS
Neurologic defects, lactic acidosis, serum alanine starting in infancy.
TREATMENT intake of ketogenic nutrients (eg, high fat content or lysine and leucine)
74
Pyruvate metabolism
Functions of different pyruvate metabolic pathways (and their associated cofactors):
Alanine aminotransferase (B6): alanine carries amino groups to the liver from muscle
Pyruvate carboxylase (B7): oxaloacetate can replenish TCA cycle or be used in gluconeogenesis
Pyruvate dehydrogenase (B1, B2, B3, B5, lipoic acid): transition from glycolysis to the TCA cycle
Lactic acid dehydrogenase (B3): end of anaerobic glycolysis (major pathway in RBCs, WBCs, kidney medulla, lens, testes, and cornea)
75
TCA cycle
Also called Krebs cycle.
Pyruvate---->acetyl-CoA produces 1 NADH, 1 CO2.
The TCA cycle produces 3 NADH, 1 FADH2, 2 CO2, 1 GTP per acetyl-CoA = 10 ATP/acetyl-CoA (2× everything per glucose).
TCA cycle reactions occur in the mitochondria.
α-ketoglutarate dehydrogenase complex requires the same cofactors as the pyruvate dehydrogenase complex (vitamins B1, B2, B3, B5, lipoic acid).
Citrate is Krebs’ starting substrate for making oxaloacetate.
76
Gluconeogenesis, irreversible enzymes
Pathway produces fresh glucose.
Pyruvate carboxylase
In mitochondria.
Pyruvate ---->oxaloacetate.
Requires biotin, ATP. Activated by acetyl-CoA.
Phosphoenolpyruvate carboxykinase In cytosol. Oxaloacetate---> phosphoenolpyruvate (PEP).
Requires GTP.
Fructose-1,6-bisphosphatase 1 In cytosol.
Fructose-1,6-bisphosphate---->fructose-6-phosphate.
Citrate ⊕, AMP ⊝, fructose 2,6-bisphosphate ⊝.
Glucose-6-phosphatase In ER. Glucose-6-phosphate-----> glucose.
77
Pentose phosphate pathway
Also called HMP shunt. Provides a source of NADPH from abundantly available glucose-6-P (NADPH is required for reductive reactions, eg, glutathione reduction inside RBCs, fatty acid and cholesterol biosynthesis). Additionally, this pathway yields ribose for nucleotide synthesis. Two distinct phases (oxidative and nonoxidative), both of which occur in the cytoplasm. No ATP is used or produced.Sites: lactating mammary glands, liver, adrenal cortex (sites of fatty acid or steroid synthesis), RBCs
78
Oxidative (irreversible)
G6P------>6 phosphogluconate
Glucose-6-pP dehydrogenase
NADPH
6 phosphogluconate-----> Ribulose-5-P
79
Nonoxidative (reversible)
F6P----->Ribose-5-P
| Transketolase
80
Glucose-6-phosphate dehydrogenase deficiency
NADPH is necessary to keep glutathione reduced, which in turn detoxifies free radicals and peroxides. Decreased NADPH in RBCs leads to hemolytic anemia due to poor RBC defense against oxidizing agents (eg, fava beans, sulfonamides, nitrofurantoin, primaquine/chloroquine, antituberculosis drugs). Infection (most common cause) can also precipitate hemolysis; inflammatory response produces free radicals that diffuse into RBCs, causing oxidative damage.
X-linked recessive disorder; most common human enzyme deficiency; more prevalent among descendants of populations in malaria-endemic regions (eg, sub-Saharan Africa, Southeast Asia).
Heinz bodies—denatured globin chains precipitate within RBCs due to oxidative stress. Bite cells—result from the phagocytic removal of Heinz bodies by splenic macrophages. Think, “Bite into some Heinz ketchup.
81
Essential fructosuria
Involves a defect in fructokinase.
Autosomal recessive. A benign, asymptomatic condition
(fructokinase deficiency is kinder), since fructose is not trapped in cells. Hexokinase becomes 1° pathway for converting fructose to fructose-6-phosphate.
Symptoms: fructose appears in blood and urine.
Disorders of fructose metabolism cause milder symptoms than analogous disorders of galactose metabolism.
82
Hereditary fructose intolerance
Hereditary deficiency of aldolase B.
Autosomal recessive. Fructose-1-phosphate accumulates, causing a in available phosphate, which results in inhibition of glycogenolysis and gluconeogenesis.
Symptoms present following consumption of fruit, juice, or honey. Urine dipstick will be ⊝ (tests for glucose only); reducing sugar can be detected in the urine (nonspecific test for inborn errors of carbohydrate metabolism).
Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting.
Treatment: intake of fructose, sucrose (glucose + fructose), and sorbitol (metabolized to fructose)
83
Galactokinase deficiency
Hereditary deficiency of galactokinase. Galactitol accumulates if galactose is present in diet. Relatively mild condition. Autosomal recessive.
Symptoms: galactose appears in blood (galactosemia) and urine (galactosuria); infantile cataracts.
May present as failure to track objects or to develop a social smile. Galactokinase deficiency is kinder (benign condition)
84
Classic galactosemia
Absence of galactose-1-phosphate uridyltransferase.
Autosomal recessive. Damage is caused by accumulation of toxic substances (including galactitol, which accumulates in the lens of the eye).
Symptoms develop when infant begins feeding (lactose present in breast milk and routine formula) and include failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability. Can predispose to E coli sepsis in neonates.
Treatment: exclude galactose and lactose (galactose + glucose) from diet
85
FAB GUT
Fructose is to Aldolase B as Galactose is to UridylTransferase .The more serious defects lead to PO43− depletion.
86
Sorbitol
Glucose------>Sorbitol
NADPH NAD+Aldose reductase
Sorbitol--------->Fructose dehydrogenase
Lens has primarily Aldose reductase. Retina, Kidneys, and Schwann cells have only aldose reductase (LARKS)
87
Lactase deficiency
Insufficient lactase enzyme---->dietary lactose intolerance. Lactase functions on the intestinal brush border to digest lactose (in milk and milk products) into glucose and galactose.
Primary: age-dependent decline after childhood (absence of lactase-persistent allele), common in people of Asian, African, or Native American descent.
Secondary: loss of intestinal brush border due to gastroenteritis (eg, rotavirus), autoimmune disease.Congenital lactase deficiency: rare, due to defective gene.Stool demonstrates pH and breath shows hydrogen content with lactose hydrogen breath test (H+ is produced when colonic bacteria ferment undigested lactose).
Intestinal biopsy reveals normal mucosa in patients with hereditary lactose intolerance
88
Amino acids
| Glucogenic/ketogenic:
Isoleucine, phenylalanine, threonine, tryptophan
89
Urea cycle
NH3----> carbamoyl-P
CPS-1+ATP AMP
AR
no orotic acidurea
Ornithine-----> citrulline
Ornithin-transcabamoylase
XR
orotic acidurea
deficeny: NH3 increases, NH4+ increases in the brain/ cerebral edema, blood, asterixes, bolging fontanelle, low BUN, increased glutamine
90
Treatment: limit protein in diet. May be given to decrease ammonia levels:
Lactulose to acidify GI tract and trap NH4+ for excretion. Antibiotics (eg, rifaximin, neomycin) to decreases ammoniagenic bacteria. Benzoate, phenylacetate, or phenylbutyrate react with glycine or glutamine, forming products that are excreted renally
91
Catecholamine synthesis/tyrosine catabolism
```
Phenylalanine------->Tyrosine
BH4
BH4B6Vitamin CSAMDopamine
Norepinephrine
EpinephrineMetanephrine
Normetanephrine
Vanillylmandelic acid Monoamineoxidase
Monoamine oxidase
```
92
Amino acid derivatives
```
Amino acid derivatives
Tryptophan
NiacinNAD+/NADP+Serotonin
MelatoninPhenylalanineNEThyroxine
Tyrosine
DopamineDopaHistidine
HistamineGlycine
PorphyrinHemeEpiArginineBH4 = tetrahydrobiopterinUreaNitric oxid
```
93
Glycogen
Branches have α-(1,6) bonds; linkages have α- (1,4) bonds
94
Skeletal muscle
Glycogen undergoes glycogenolysis---->glucose-1-phosphate--->glucose-6-phosphate, which is rapidly metabolized during exercise.
95
Hepatocytes
Glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels. Glycogen phosphorylase liberates
glucose-1-phosphate residues off branched glycogen until 4 glucose units remain on a branch. Then
4-α-d-glucanotransferase (debranching enzyme ) moves 3 of the 4 glucose units from the branch to the linkage. Then
α-1,6-glucosidase (debranching enzyme ) cleaves off the last residue, liberating glucose.“Limit dextrin” refers to the two to four residues remaining on a branch after glycogen phosphorylase has already shortened it.
96
Fatty acid metabolism
Fatty acid synthesis requires transport of citrate from mitochondria to cytosol. Predominantly occurs in liver, lactating mammary glands, and adipose tissue.
Long-chain fatty acid (LCFA) degradation requires carnitine-dependent transport into the mitochondrial matrix.
```
“Sytrate” = synthesis.
Carnitine = carnage of fatty acids.
```
Systemic 1° carnitine deficiency—no cellular uptake of carnitine---->no transport of LCFA s into mitochondria----->toxic accumulation of LCFAs in the cytosol. Causes weakness, hypotonia, hypoketotic hypoglycemia, dilated cardiomyopathy.
Medium-chain acyl-CoA dehydrogenase deficiency— decreases ability to break down fatty acids into acetyl-CoA-----> accumulation of fatty acyl carnitines in the blood with hypoketotic hypoglycemia. Causes vomiting, lethargy, seizures, coma, liver dysfunction, hyperammonemia. Can lead to sudden death in infants or children. Treat by avoiding fasting.
97
Hormone-sensitive lipase
Degrades TGs stored in adipocytes. Promotes gluconeogenesis by releasing glycerol.
98
Lipoprotein lipase
Degrades TGs in circulating chylomicrons
99
Glycogen storage diseases
Periodic acid–Schiff stain identifies glycogen and is useful in identifying these diseases
ABCD
Andersen: Branching.
Cori: Debranching.
100
Ketone bodies
With chronic alcohol overuse, excess NADH shunts oxaloacetate to malate. All of these processes lead to a buildup of acetyl-CoA, which is shunted into ketone body synthesis.
101
Fed state (after a meal)
Glycolysis
and aerobic respiration. Insulin stimulates storage of lipids, proteins, and glycogen.
102
Fasting (between meals)
Hepatic glycogenolysis (major); hepatic gluconeogenesis,
adipose release of FFA (minor). Glucagon and epinephrine stimulate use of fuel reserves.
103
Starvation days 1–3
Blood glucose levels maintained by:
Hepatic glycogenolysis
Adipose release of FFA
Muscle and liver, which shift fuel use from glucose to FFA
Hepatic gluconeogenesis from peripheral tissue lactate and alanine, and from adipose tissue glycerol and propionyl-CoA (from odd-chain FFA—the only triacylglycerol components that contribute to gluconeogenesis)
Glycogen reserves depleted after day 1.
104
Starvation after day 3
Adipose stores (ketone bodies become the main source of energy for the brain).
After these are depleted, vital protein degradation accelerates, leading to organ failure and death. Amount of excess stores determines survival time.
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