21 April 2010


By: Henry Wormser, Ph.D.

* Definition: water insoluble compounds
+ Most lipids are fatty acids or ester of fatty acid
+ They are soluble in non-polar solvents such as petroleum ether, benzene, chloroform
* Functions
+ Energy storage
+ Structure of cell membranes
+ Thermal blanket and cushion
+ Precursors of hormones (steroids and prostaglandins)
* Types:
+ Fatty acids
+ Neutral lipids
+ Phospholipids and other lipids
Fatty acids
* Carboxylic acid derivatives of long chain hydrocarbons
o Nomenclature (somewhat confusing)
+ Stearate – stearic acid – C18:0 – n-octadecanoic acid
o General structure:
* Common fatty acids
n = 4 butyric acid (butanoic acid)
n = 6 caproic acid (hexanoic acid)
n = 8 caprylic acid (octanoic acid)
n = 10 capric acid (decanoic acid)
* common FA’s:

n = 12: lauric acid (n-dodecanoic acid; C12:0)
n = 14: myristic acid (n-tetradecanoic acid; C14:0)
n = 16: palmitic acid (n-hexadecanoic acid; C16:0)
n = 18; stearic acid (n-octadecanoic acid; C18:0)
n = 20; arachidic (eicosanoic acid; C20:0)
n= 22; behenic acid
n = 24; lignoceric acid
n = 26; cerotic acid

Less common fatty acids
* iso – isobutyric acid
* anteiso
* odd carbon fatty acid – propionic acid
* hydroxy fatty acids – ricinoleic acid, dihydroxystearic acid, cerebronic acid
* cyclic fatty acids – hydnocarpic, chaulmoogric acid

A plant derived fatty acid with 16 carbons and branches at C 3, C7, C11 and C15. Present in dairy products and ruminant fats.
A peroxisome responsible for the metabolism of phytanic acid is defective in some individuals. This leads to a disease called Refsum’s disease
Refsum’s disease is characterized by peripheral polyneuropathy, cerebellar ataxia and retinitis pigmentosa
Less common fatty acids
These are alkyne fatty acids
Fatty acids
* Fatty acids can be classified either as:
o saturated or unsaturated
o according to chain length:
Unsaturated fatty acids
* Monoenoic acid (monounsaturated)
Double bond is always cis in natural fatty acids.
This lowers the melting point due to “kink” in the chain
* Dienoic acid: linoleic acid
* Various conventions are in use for indicating the number and position of the double bond(s)
* Polyenoic acid (polyunsaturated)
* Monoenoic acids (one double bond):
* Trienoic acids (3 double bonds)
* Tetraenoic acids (4 double bonds)
* Pentaenoic acid (5 double bonds)
* Hexaenoic acid (6 double bonds)
Both FAs are found in cold water fish oils
Typical fish oil supplements
Properties of fats and oils
* fats are solids or semi solids
* oils are liquids
* melting points and boiling points are not usually sharp (most fats/oils are mixtures)
* when shaken with water, oils tend to emulsify
* pure fats and oils are colorless and odorless (color and odor is always a result of contaminants) – i.e. butter (bacteria give flavor, carotene gives color)
Examples of oils
* Olive oil – from Oleo europa (olive tree)
* Corn oil – from Zea mays
* Peanut oil – from Arachis hypogaea
* Cottonseed oil – from Gossypium
* Sesame oil – from Sesamum indicum
* Linseed oil – from Linum usitatissimum
* Sunflower seed oil – from Helianthus annuus
* Rapeseed oil – from Brassica rapa
* Coconut oil – from Cocos nucifera.....

Websites on lipids

* http://www.cyberlipid.org/ web site deals mainly with an overview on all lipids
* http://www.lipidsonline.org – this website focuses mainly on disease processes (atherosclerosis) and treatment
* http://www.lipidlibrary.co.uk/ -There are two main divisions in this website, one dealing with the chemistry and biochemistry of lipids and the other with the analysis of lipids



Inborn Errors of Metabolism

Inborn Errors of Metabolism
By:Namrata Singh M.D

Introduction to IEM
* Usually a single gene defect that causes a block in metabolic pathways.
* Problems are because of accumulation of enzyme substrate behind the metabolic block or deficiency of the reaction product.
* In some instances the substrate is diffusible & affects distant organs & in some there is just a local effect ( lysosomal storage disease ).
* Clinical presentation is varied  mild to severe forms ( mutations even in the same gene may be different in different people ).
* Can present at any time.
* Can affect any organ system.

IEM General approach
* DIAGNOSIS : Some clinical presentations:-
o Consider in DDx . when dealing with :-
+ Critically ill infant
+ Seizures
+ Encephalopathy (Reyes like syndrome )
+ Liver disease
+ MR or developmental delay or regression
+ Recurrent vomiting
+ Unusual odor
+ Unexplained acidosis
+ Hyperammonemia
+ hypoglycemia
* Some clues to look for :-
o *Symptoms accompany changes in diet.
o *Developmental regression.
o *History of food preferences or aversions.
o *History of consanguinity in parents.
o *Family history of MR , unexplained deaths in cousins or siblings etc.
* Physical exam:- common findings—
o Alopecia or abnormal hair
o Retinal cherry red spot
o Cataracts or corneal opacities
o Hepatosplenomegaly
o Coarse features
o Skeletal changes ( gibbus)
o Ataxia
o Micro or macrocephaly
o Rash / jaundice /hypo or hypertonia
* Lab tests:- almost always needed—
o Serum electrolytes
o Ph ( anion gap & acidosis )
o Se lactate
o Se pyruvate
o Ammonia
o Serum & urine amino acids
o Urine organic acids
o DNA probes
o Glycine in CSF (glycine encephalopathy)
o Urine ketones
+ If + in neonates  IEM
+ If – in older child  IEM ( defect in f.a. oxidation )

IEM – Clinical situations
* MR or dev delay
o Can occur alone.
o Seen in urea cycle ,a.a disorders.
o Also in organic acidemias ,peroxisomal & lysosomal storage disorders.
o Serum & urine a.a .
o Urine for mucopolysacchiduria.
* Ill neonate :-
o Clinically indistinguishable from sepsis.
o Usually disorders of protein & CHO metabolism.
o Acidosis or altered mental status out of proportion to systemic symptoms.
o Labs:
+ Lytes , NH3, gluc , ketones , urine ph ,glycine in CSF.
+ Se & urine for a.a & o.a (* before oral intake is stopped or pt is transfused)

IEM – Clinical situations
* Vomiting & encephalopathy :-
* Hypoglycemia :-
o Seen in fatty acid oxid defects ,glycogen storage diseases ,hereditary fructose intolerance & organic acidemias.
o Other labs:-
Urine ketones ~(+) in GSD & organic acidemias. ~(-) in HFI & f.a. oxidation disorders
o Other labs:-
+ NH3 elevated in organic acidemias & fatty acid oxidation defects.
+ Urine reducing subst.– (+) in galactosemia ,HFI.
+ Urine organic acids
* Hyperammonemia :-
o initially – poor appetite , irritability . Then , vomiting , lethargy , seizures & coma.
o Tachypnea – direct effect on resp. drive.
o Seen in (1)- urea cycle disorders (2)- organic acidemias (3)- transient hyperammonemia of the newborn.
o Resp alkalosis : urea cycle disorders & transient hyperammonemia of newborn.
o Acidosis : organic acidemias

* Acidosis :-
o With recurrent vomiting.
o With elevated NH3.
o Out of proportion to clinical picture.
o Difficult to correct.
o Seen in organic acidemias , MSUD ,GSD , disorders of gluconeogenesis.
o Increased anion gap (ketoacids ,lactic acid , methylmalonic acid.)

* Acidosis :- additional tests—
o Se glucose
o NH3
o Urine pH
o Ketones
o Amino & organic acids
o Blood lactate & pyruvate
* Lactate & pyruvate—
o Measure in arterial blood.
o Normal Ratio is 10:1 to 20:1.
o High ratio
+ Mitochondrial disorders.
+ Pyruvate carboxylase deficiency.
o Normal or low ratio
+ Glycogen storage disease.
+ Pyruvate dehydrogenase deficiency
* Broad management :-
o Problems severe acidosis , hypoglycemia , hyperammonemia . Can lead to coma & death!
o Stop all oral intake.
o Give I/V glucose to stop catabolism.( most respond favorably to glucose – some do not eg. Primary lactic acidosis in pyruvate dehydrogenase deficiency .)
o Bicarb.
o Hyperammonemia – may need dialysis .
* Specific interventions :-
o Urea cycle disorders-
+ * preventing protein catabolism ( high calorie diet , arginine supplementation )
+ * decreasing NH3 load (protein restriction )
+ * utilizing NH3 scavengers ( benzoate ,phenylbutyrate)
o PKU-
+ *Avoid enzyme substrate in diet.
+ *Diet low in phenylalanine ( Lofenelac , Phenylfree, Analog XP , Maxamaid XP )
+ *Protein restriction.
o Galactosemia-
+ *galactose free diet ( soy formulas contain sucrose rather than lactose )
o Isovaleric acidemia-
+ Pharmacotherapy to remove accumulated substrate –( glycine treatment).
o Methylmalonic acidemia-
+ Provide co-enzyme ( vit B12)
o Gauchers disease-
+ Provide normal enzyme (enzyme infusions)

IEM Some associations

Inborn Errors of Metabolism.ppt


Complex Carbohydrates

Complex Carbohydrates

- Know the structural components and differences between the glycoconjugate types
- Know the general biosynthetic and catabolic strategies and molecules involved
- Know the general function of each class of glycoconjugate
- Know the general biochemical principles associated with diseases resulting from defects in the catabolic pathways of the glycoconjugates

* Marks, Marks and Smith Chapter 30, primary source, Harper’s Ch 56 supersecondary source. Review Ch. 15,16 for sugar and lipid structural properties

General Biosynthetic and Catabolic Themes for Glycoconjugates
* An initial sugar residue is attached to a core protein or lipid, usually through a serine or asparagine residue.
* Sugar residues are added sequentially from nucleotide diphosphate sugar donors by specific glycosyltransferases in the endoplasmic reticulum and golgi.
* Glycosidases (sugar specific hydrolases) in the lysosome are responsible for degradation and catabolism
* Almost all diseases related to glycoconjugates result from defective lysosomal glycosidase function

UDP-Glucose Glycosyltranserase Reaction
Sugar Nucleotide Conversions
* Consist of a core protein, that is either transmembranous or secreted. Via serine residues, long, unbranched, repeating disaccharides of uronic acid (glucuronic or iduronic) and hexosamine (N-acetylglucosamine or N-acetylgalactosamine) are covalently attached to the protein on the (on the extracellular surface if membrane attached).
* These residues are frequently sulfated following polymer formation. Thus they possess a large net negative charge, are highly hydrated, and occupy a large amount of space extracellularly (good for their role as lubricants and molecular sieves). They also provide a large surface area for binding of other matrix components and some growth factors.
* Major components of the extracellular matrix, also in joint synovial fluid, vitreous humor of the eye, arterial walls, bone and cartilage

The main classes of disaccharide repeats found in glycosaminoglycans attached to protein
GAG-Carbohydrate Core Linkage to Protein

Sequential Biosynthetic Pathway for GAGs
There are three major classes of glycoproteins – those with carbohydrate chains that are N-linked (via an Asn), O-linked (via Ser or Thr) or linked via a glycosylphosphatidylinositol (GPI) lipid. These are primarily transmembranous proteins with the carbohydrates positioned extracellularly, and they are also secreted.

* For N-linked, the carbohydrate core structure is synthesized processively on an activated lipid carrier, dolichol phosphate, and transferred co-translationally to membrane proteins synthesized in the endoplasmic reticulum.

Three Main Types of Glycoprotein Structures
GPI = glycosylphosphatidylinositol
Also: targeting signal for removal of damaged or mis-folded proteins from the cell
And: generally function to aid in the proper conformation and stability of membrane-associated proteins
Dolichol-linked Donor Oligosaccharide Synthesis for N-linked Glycoproteins
O-linked Glycoproteins (Mucins most common)
* Carbohydrates are attached to ceramide (a sphingolipid: sphingosine plus fatty acid). Involved in cell-cell contact/interactions. The terminal carbohydrates can frequently be identical to carbohydrate chains on glycoproteins (Ex: blood group antigens)
* Cerebrosides – glycolipids with one or two sugars (glucose and galactose); if sulfated, are termed sulfatides, found in high concentrations in the brain
* Gangliosides – glycolipids that contain sialic acid residues, longer and branched relative to cerebrosides

Glycolipid Structural
Sulfate donor
R = protein or ceramide
Bacteria sp. with binding proteins (lectins) for Lactosylceramide
I-Cell Disease Summary
Tay-Sachs Disease (Ex.)
* The most common form of GM2 gangliosidosis; the GM2 ganglioside accumulates due to a defect in hexosaminidase A. Causes swelling and loss of ganglion cells in the cerebral cortex, proliferation of glial cells, and demyelination of peripheral nerves.
* Rare defect in general population, but occurs 1 in every 3600 births in the U.S. Jewish population descended from Eastern Europe (ex: 1 in 28 Ashkenazi Jews carry the defect).
* No effective treatments; genetic counseling and screening are the primary approaches used to minimize occurrence.

Complex Carbohydrates


Sphingolipid Disorders

Sphingolipid Disorders
by:Eric Niederhoffer

Sphingolipids (phospho- or glycolipids)

General Structure
Generalized gangliosidosis
Tay-Sachs disease
Niemann-Pick disease
Metachromatic leukodystrophy
Krabbe’s disease
Gaucher’s disease
b-hexosaminidase A
GM2 activator
b-hexosaminidase A&B
a-galactosidase A
arylsulfatase A
Targeting of Lysosomal Enzymes to Lysosomes
Addition of M6P to lysosomal enzymes
Recognition by MPRs
M6P independent pathways

Review Questions

* How do you interpret ganglioside names (G, D, M, 1, 2, 3)?
* What do the different lysosomal enzyme names mean in the context of removing saccharides?
* Where does ganglioside degradation occur?

Sphingolipid Disorders

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