GluCer / GalCer isoforms (continued), Gangliosides, Sphingolipid pathway

• the transfer of glucose from UDP-glucose to ceramide → to produce glucosylceramide

GlcCer (Glucosylceramide)

• isoforms
  • GluCer is comprised of different isoforms owing to differen fatty acid moieties.
  • GluCer isoforms are isobaric structural isomers of galactosylceramide (GalCer) isoforms
  • GalCer has similar chemical properties as GluCer but is not a substrate of GCase.
  • Both species can be differentiated only by the axial or equatorial configuration of one hydroxyl group
• Normal range
  • CSF : 4.5—5.9 5.9 μg/mL ng/mL의 typo?(venglustat P2 LEAP trial)

glucosylsphingosine (lyso-Gb1), a downstream metabolic product of glucosylceramide, a deacylated form of glucosylceramide, is also degraded by the glucocerebrosidase. β-glucocerebrosidase enzyme catalyzes the metabolism of glycosphingolipids

Figure 1 caption (under the GluCer / GalCer chemical-structure pair):

Figure 1. Structures of (A) glucosylceramide (GluCer) and (B) galactosylceramide (GalCer). Both molecules are comprised of different isoforms according to different fatty acid chains. The cleavage site of the glucocerebrosidase (GCase) enzyme is indicated on the GluCer molecules. Red circles indicate the hydroxyl group differentiating GluCer and GalCer by its axial or equatorial configurations. Glu = glucose, Gal = galactose.

Gangliosides

Main source: (Kolter 2012, PMID 25969757)

• ⊞Js Conclusion: gangliosides are formed from GlcCer and ceramide, so it is hard to predict whether GBA loss will lead to increase or reduce gangliosides.

Expression	most abundant GSLs in the CNS, predominantly in the nervous system where they constitute 6% of all phospholipids.[3], especially abundant in the brain, where their occurrence in the grey matter is about 5-fold higher than in white matter Gangliosides are also found in serum. There, especially GM3, GD3, GD1a, GM2, GT1b, sialylneolactotetraosylceramide (Figure 10), GD1b, and GQ1b are present, where about 98% of them are transported by serum lipoproteins, predominantly by LDL (66%), followed by HDL (25%) and VLDL (7%) [69].
Location	a component of the cell plasma membrane that modulates cell signal transduction events, and appears to concentrate in lipid rafts
Definition & Structure	complex GSLs (glycosphingolipid), composed of a glycosphingolipid (ceramide and oligosaccharide) with one or more sialic acids (e.g. n-acetylneuraminic acid, NANA) linked on the sugar chain 즉 다음 세 부분의 결합체

ceramide	Oligosaccharide (=glycan)	more sialic acids (e.g. n-acetylneuraminic acid, NANA)
Ceramide is the common precursor of GSLs and sphingomyelin and is transported to the Golgi apparatus at least in part in a protein-dependent manner by the transport protein CERT [135-137].

examples	More than 60 gangliosides are known,
		One NANA ("M")	Two NANAs ("D")	Three NANAs ("T")	Four NANAs ("Q")
	series	a	b	c Only trace
		GM1 (abundant, if ↓ GM1 → ↑ PD, ↑ GM1 → ↓ PD, ↓ aggregation of a-syn to cytotoxic fibrills) GM2 GM3	GD1a(abundant) GD1b(abundant) GD2 GD3	GT1b(abundant) GT3	GQ1 (abundant, is involved in LTP, synaptic plasticity, and cognitive function)
Function	essential for myelination, neuritogenesis, synaptogenesis and signalling of the neurotrophic factor GDNF [42-44].
pathology	A reduction in GM1a levels was described in SN and occipital cortex from PD patients (GBA loss시 ↓ Ceramide 니까 이것도 주나보다) (Gangliosidosis의 예) Tay-Sacks disease: a genetic defect which leads to no functional hexosaminidase A produced → GM2 to accumulate in lysosomes → ganglion cells in the nervous system swell enormously, disturbing the normal functions of neurons.[3]
Synthesis	De novo synthesis (적음?)
		Steps
		1	Ganglioside biosynthesis starts with the formation of ceramide (Figure 9) at the cytoplasmic leaflet of the ER membrane [124-126]. The first step, the condensation of L-serine and a coenzyme A-activated fatty acid is catalyzed by the pyridoxal phosphate-dependent serine palmitoyltransferase (SPT The next step in sphingolipid biosynthesis is the NADPH-dependent reduction of 3-ketosphinganine to sphinganine by 3-ketosphinganine reductase, followed by acylation of sphinganine to dihydroceramides of different chain lengths [131]. During salvage, also other sphingoid bases are acylated by N-acyltransferases of the lass family. Dihydroceramides are dehydrogenated to ceramide by the dihydroceramide desaturase des1 [134], or hydroxylated to phytoceramides by des2.
		2	stepwise transfer of nucleotide-activated monosaccharide units first on ceramide with growing glycan chains.
		3	stepwise transfer of nucleotide-activated monosaccharide units on GSLs with growing glycan chains.
	The B4GALNT1 gene encodes the enzyme, ((Huebecker et al. 2019, PMID 31703585) this encodes GM2 synthase) β-1,4-N-acetyl galactosaminyltransferase 1 (GalNac-T), which catalyzes the transfer of N-acetyl galactosamine onto GM3 and GD3 gangliosides → resulting in GM2 and GD2 → that then undergo further metabolism into GM1 and GD1 (Forsayeth and Hadaczek 2018, PMID 29459819)

Salvage pathway / Degradation

	[salvage pathway (from recycling): this can be predominant undifferentiated cells (?)]
	Steps
	1	GlcCer 생성 (원래 알고 있는 pathway) on the cytoplasmic face of Golgi (membrane) (by Transfer of a glucose residue from UDP glucose to ceramide)
	2	GlcCer is translocated to the luminal site of the Golgi membrane
	3	LacCer is formed from GlcCer (by galactosyltransferase I) LacCer and its sialylated derivatives, the hematosides GM3, GD3, and GT3 (Figure 11) serve as precursors for complex gangliosides of the O-, a-, b-, and c-series. part of the GlcCer pool can reach the cytosolic leaflet of the plasma membrane where it can be degraded by the β-glucosidase Gba2 [185
Degradation	degraded to ceramides by sequential removal of sugar units in the oligosaccharide group, catalyzed by a set of highly specific lysosomal enzymes.

Sphingolipid base structure

Sphingolipid figure labels: Sphingosine (C18), fatty acid, head group, Sphingolipid.

Name	X=
Ceramide	H
Sphingomyelin	~P~Choline ~P~Ethanolamine
Glucosylcerebroside	—Glc (in non-neural tissue)
Galactocerebroside	—Gal (in neural tissue)
Globosides	several neutral sugars (Glc, Gal, GalNAc)
Gangliosides	complex carbohydrates: GM: single NANA GD: two NANA GT: three NANA GQ: four NANA

N-acetylneuraminic acid (NANA) figure label: N-acetylneuraminic acid (NANA).

Ganglioside / globoside degradation cascade (figure labels)

• GM1 → Ceramide–Glc–Gal–GalNAc–Gal, side branch NANA; arrow with enzyme β-galactosidase, disease GM1 gangliosidosis, releasing Gal.
• GM2 → Ceramide–Glc–Gal–GalNAc, side branch NANA; arrow with enzyme hexosaminidase A, disease Tay-Sachs disease, releasing GalNAc.
• GM3 → Ceramide–Glc–Gal, side branch NANA; arrow with enzyme ganglioside neuraminidase, releasing NANA.
• Globoside → GalNAc–Gal–Gal–Glc–Ceramide; arrow with enzyme hexosaminidase A + B, disease Sandhoff-Jatzkewitz's disease, releasing GalNAc.
• Gal–Gal–Glc–Ceramide → Ceramide–Glc–Gal; arrow with enzyme alpha-galactosidase A, disease Fabry's disease, releasing Gal.
• Ceramide–Glc–Gal → …; arrow with enzyme β-galactosidase, releasing Gal.
• Sphingosine ← ceraminidase Farber's disease ← Ceramide
• Ceramide → Glc Gaucher's disease
• Sphingomyelin ↔ CholinePCeramide ↔ Ceramide via sphingomyelinase Niemann-Pick disease

Uncertain Spans

location	transcription	uncertainty
Synthesis step 1	pyridoxal phosphate-dependent serine palmitoyltransferase (SPT	the closing ) after SPT is missing in the source.
GQ1 examples cell	GQ1	reads as written; statusbar earlier OCR alternated with GQ1b but the visible cell reads GQ1.